Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13](N)=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.N([O-])=O.[Na+].[Na+].[I-:22]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([I:22])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(N)ccc2s1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(I)ccc2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 5-amino-benzo[b]thiophene-2-carboxylic acid ethyl ester (18.37 g, 83.02 mmol) was added an aqueous HCl solution (21 mL conc. HCl in 200 mL H2O, 252 mmol)) and the resulting mixture was cooled to 0° C. A solution of NaNO2 (6.02 g in 60 mL H2O, 87.25 mmol) was added and the mixture was allowed to stir at 0° C. for 10 min. A solution of NaI (13.07 g in 60 μL H2O, 87.20 mmol) was added slowly. The reaction mixture became difficult to stir during the addition of NaI. A total of 300 mL of water was added in several portions. After the addition was complete, the reaction was warmed to rt and allowed to stir at rt for 2 h. The mixture was then diluted with CH2Cl2 (800 mL) and water (100 mL). The organic layer was separated, washed with 200 mL of saturated NaHCO3 and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was filtered through a pad of silica gel, washing with EtOAc/hexanes (0% to 10%). The filtrate was then concentrated and the residue was recrystallized from MeOH to give 5-iodo-benzo[b]thiophene-2-carboxylic acid ethyl ester as light orange solid. MS (EI): cal'd 332.9 (MH+), exp 333.1 (M+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([S:7]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of (5-bromo(2-thienyl))chlorosulfone (1.09 g, 4.16 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.4 mL, 3.052 mmol), followed by (4-fluorophenyl)piperazine (500 mg, 2.77 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was treated with a saturated NaHCO3 solution (1 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with a saturated NaCl solution (10 mL), dried (MgSO4) and concentrated under reduced pressure to give a brown solid. The crude product was purified flash chromatography (10% EtOAc/hex) to give 5-bromo-2-{[4-(4-fluorophenyl)piperazinyl]sulfonyl}thiophene (1.12 g, 100%) as a white solid: mp 123-124° C.; TLC (EtOAc) Rf 0.44; HPLC ES-MS m/z 406 (MH+).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1>ClCCl.O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][C:14]=1[Br:1]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(Br)c1
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water. The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88% yield), identified by HNMR and mass spectral analyses. MS m/e 242 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3H), 4.22 (q, J=7.16 Hz, 2H), 6.18 (brs, 2H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1H), 7.89 (d, J=1.83 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C(Cl)Cl.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
2-Bromobenzenesulfonyl chloride (100.9 g, 394.9 mmol) was dissolved in methylene chloride (500 mL, 8.0 mol) and cooled at 0° C. t-Butylamine (41.3 mL, 395 mmol) was added in 3 portions over approximately 1 minute. DIPEA (75.7 mL, 434 mmol) was immediately added in 3 portions over approximately 1 minute. The mixture was warmed to room temperature and stirred overnight. The product was washed with 1M H3PO4 (2×), with saturated. NaHCO3, and with saturated aqueous NaCl, then dried over MgSO4, filtered, and concentrated to yield 2-bromo-N-t-butyl-benzenesulfonamide (112 g) as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH2:9].[BrH:16].BrBr>O>[NH2:9][C:8]1[C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][C:7]=1[Br:16]
Reactant: Nc1ccc(S(N)(=O)=O)cc1C(F)(F)F
Reactant: Br
Agent: BrBr
Solvent: O
Product: Nc1c(Br)cc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
A suspension of 0.69 g. (0.029 moles) of 3-trifluoromethyl-4-aminobenzenesulfonamide in 7 ml. of water and 7 ml. of 48% hydrobromic acid is treated dropwise with 0.16 ml. of liquid bromine and stirred for 3 hours at room temperature. The reaction mixture is filtered, the solid material washed with 10% aqueous sodium bicarbonate, water and dried. The dried solid is recrystallized from toluene affording 0.76 g. of 4-amino-3-bromo-5-trifluoromethylbenzenesulfonamide, m.p. 248°-252° C.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CC[N:27](C(C)C)C(C)C.[CH:34]1([CH:37]2[CH2:41][CH2:40][N:39](N)[CH:38]2[CH3:43])[CH2:36][CH2:35]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH:34]5[CH2:36][CH2:35]5)[C:38]4([CH3:43])[NH2:27])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC1C(C2CC2)CCN1N
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(C5CC5)C4(C)N)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-cyclopropyl-methyl-amino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 4H). m/z: 472 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([CH2:24][CH3:25])[C:20]([N+:21]([O-])=O)=[C:16]2[CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>C(O)C.O.[Zn]>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([CH2:24][CH3:25])[C:20]([NH2:21])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1nn2c(-c3c(OC)cc(C)cc3OC)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCc1nn2c(-c3c(OC)cc(C)cc3OC)cccc2c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
After dissolving 7-(2,6-dimethoxy-4-methylphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (600 mg) in a mixture of ethanol (30 mL) and water (30 mL), acetic acid (3 mL) and zinc powder (600 mg) were added and the mixture was stirred at 60° C. for 2 hours. The ethanol of the obtained reaction mixture was distilled off under reduced pressure, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the residue and extraction was performed with ethyl acetate. The obtained organic layers were combined, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridine-3-amine (500 mg) as a crude product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (36%, white crystals). HPLC-MS m/z=389.1 (M+1), Rt: 5.13 min.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:12]=[CH2:13])(C)C.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li+].[CH2:22]1COCC1>>[CH3:22][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:11]([O:10][C:5]2[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=[CH2:13])=[CH:17][CH:16]=1
Reactant: C=CCOc1ccccc1C(C)C
Reactant: C1CCOC1
Reactant: [O-]c1ccccc1
Agent: [Li+]
Product: C=CC(Oc1ccccc1)c1ccc(OC)cc1
Reaction time: 14 h

Procedure:
(−)-i-Propyl allyloxybenzene (Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012): The general procedure was followed with lithium phenoxide (200 mg, 2.0 mmol) and 2-hexenyl methylcarbonate (160 mg, 1.0 mmol) in THF (2 mL). The reaction was conducted at 50° C. for 14 h. 1H NMR analysis of the mixture indicated the ratio of regioisomers to be 92/8. The residue was purified by flash chromatography on silica gel (0-1% Et2O/Hexanes) to afford 162 mg of the title compound as an oil. [93%, Rf 0.90 (5% Et2O/Hexanes)]. 1H NMR (500 MHz, CDCl3) δ 7.23 (m, 2H), 6.91 (m, 3H), 5.84 (ddd, J=17.3, 10.6, 6.2 Hz, 1H), 5.25 (d, J=17.4 Hz, 1H), 5.20 (d, J=10.6 Hz, 1H), 4.59 (dt, J=6.8, 6.0 Hz, 1H), 1.83-1.74 (m, 1H), 1.68-1.61 (m, 1H), 1.58-1.38 (m, 2H), 0.96 (t, J=7.4 Hz, 3H); 13C NMR (125.77 MHz, CDCl3) δ 158.4, 138.2, 129.3, 120.6, 116.2, 116.0, 78.6, 37.7, 18.6, 14.0. HPLC analysis indicated an enantiomeric excess of 92% [Chiralcel® OD-H column, eluting with 99.9:0.1 hexane/i-PrOH, 0.6 mL/min, 220 nm; major enantiomer tR, 13.3, minor enantiomer tR 15.8 min].
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:46]=[CH:45][C:10]2[C:11]3[S:32][C:31]4[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][C:30]=4[C:12]=3[CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)[O:14][C:9]=2[CH:8]=1)(=O)=O.C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1.C(O)=O.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:24]1([CH2:23][CH2:22][O:21][C:18]2[CH:17]=[CH:16][C:15]([CH:13]3[C:12]4[C:30]5[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=5[S:32][C:11]=4[C:10]4[CH:45]=[CH:46][CH:7]=[CH:8][C:9]=4[O:14]3)=[CH:20][CH:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=S(=O)(Oc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)c1c-2sc2cc(OS(=O)(=O)C(F)(F)F)ccc12)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCP(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)c1c-2sc2ccccc12
Yield: 57 %

Procedure:
A solution of the product of Example 6 (780 mg, 1.06 mmol), palladium(II) acetate (42 mg, 0.19 mmol), 1,2-bis(diphenylphosphinopropane (149 mg, 0.36 mmol), formic acid (0.6 mL), and triethylamine (3.0 mL) in anhydrous dimethylformamide (40 mL) was stirred at ambient temperature for 4 d. After concentration, the residue was subjected chromatography (silica gel, 1:1 hexane:ethylacetate, 2-10% methanol, 0.1% ammonium hydroxide). Product containing fractions were concentrated, partitioned between methylene chloride (100 mL) and saturated sodium bicarbonate (100 mL), and the aqueous layer extracted with methylene chloride (50 mL). The combined organic extracts were dried (sodium sulfate), concentrated, and the residue purified by chromatography (silica gel, 1:1 hexane:ethylacetate, 2-10% methanol, 0.1% ammonium hydroxide) to give 267 mg (57%) of the title compound as an oil which gave a white, crystalline solid, mp 107° C., upon trituration with ether/hexane: 1H NMR (300 MHz, CDCl3) d 7.86 (d, J=7.4 Hz, 1H), 7.40 (m, 1H), 7.1-7.3 (m, 6H), 6.97 (t, J=7.3 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.66 (s, 1H), 4.07 (t, J=6.1 Hz, 2H), 2.75 (t, J=6.1 Hz, 2H), 2.49 (m, 4H), 1.5-1.7 (m, 4H), 1.4-1.5 (m, 2H); 13C NMR (125 MHz, CDCl3) d 159.1, 151.6, 139.3, 137.1, 133.0, 131.5, 129.8, 129.1, 126.8, 124.6, 124.4, 123.7, 122.6, 121.5, 121.5, 119.3, 116.9, 114.6, 77.6, 65.7, 57.7, 54.9, 25.8, 24.0; MS (FD+) m/e 441 (M+); Anal. calc'd for C28H27NO2 S: C, 76.15; H, 6.17; N, 3.17. Found: C, 75.93; H, 6.44; N, 3.01.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1.[CH3:17][O:18][C:19](=[O:31])[C@H:20]([N:28]=[C:29]=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][O:18][C:19](=[O:31])[C@H:20]([NH:28][C:29]([O:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1)=[O:30])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCc1cc2cc(-c3ccsc3)ccc2o1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccsc3)ccc2o1
Temperature: 50 °C
Yield: 47.6 %

Procedure:
A mixture of 2-hydroxymethyl-5-thiophen-3-yl-benzofuran 22 (0.31 g, 1.35 mmole), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.33 g, 1.6 mmole), triethylamine (0.43 ml), and THF (25 ml) was heated to 50° C. under a nitrogen atmosphere for 14 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography giving about 0.28 g of (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenylpropionic acid methyl ester 23, mp. 105-106° C.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>[Cl:6][C:7]1[N:11]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: C1=COCCC1
Reactant: Clc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Clc1nc2ccccc2n1C1CCCCO1
Reaction time: 2.5 h
Yield: 104.8 %

Procedure:
A 10 l reactor is charged, under argon and with stirring, with 2.5 l of THF, 180 g of 2-chlorobenzimidazole (1.18 mol) and 325 ml of 3,4-dihydro-2H-pyran (6.56 mol, 3 eq.). The reactor is heated until dissolution occurs (temperature of the mixture: 40° C.). Then 6.3 g of para-toluenesulphonic acid (0.033 mol, 0.028 eq.) are introduced. The temperature is held at between 49 and 52° C. for 2.5 h. Cooling takes place at 12° C. and 7.65 g of sodium methoxide (0.142 mol, 0.12 eq.) are added, with stirring maintained for a total time of 15 min. The temperature is then taken to 18° C., 5 l of n-heptane are added, and the whole mixture is filtered on 300 g of Clarcel FLO-M, the retentate being washed with 5 l of n-heptane. The filtrate is concentrated to dryness under reduced pressure to give 292.6 g of 2-chloro-1-(tetrahydro-pyran-2-yl)-1H-benzimidazole in the form of a slightly yellow oil (quantitative yield). 1H NMR (400 MHz, DMSO-d6): 1.42 to 2.01 (m, 5H); 2.21 to 2.34 (m, 1H); 3.69 to 3.78 (m, 1H); 4.12 (d, J=11.4 Hz, 1H); 5.72 (dd, J=2.4 and 11.2 Hz, 1H); 7.22 to 7.34 (m, 2H); 7.82 (d. J=72 Hz, 1H); 7.78 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].C1C[O:36][CH2:35][CH2:34]1>>[C:29]([N:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)[C:35](=[O:36])[CH3:34])(=[O:31])[CH3:30]
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) in THF (4 mL) was added triethylamine (0.12 mL, 0.85 mmol). The mixture was cooled in an ice bath and a solution of acetyl chloride (0.067 ml, 0.85 mmol) in THF (1 ml) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. Chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound (160 mg, 62%) as a light yellow oil. MS: m/e=367.4 [M+H]+.
Reaction SMILES: [C:1]12([CH:11]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13]([O:17][C:18](=[O:35])[CH:19]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=1[NH2:34])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:13]([O:17][C:18](=[O:35])[CH:19]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=1[NH:34][CH2:11][C:1]12[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1NCC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
To a solution of adamantane-1-carbaldehyde (3.77 g, 23 mmol) in acetic acid (45 ml) was added 2-(2-amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (4.44 g, 11.5 mmol) followed by addition of sodium triacetoxyborohydride (3.41 g, 16 mmol). The reaction mixture stirred for 30 minutes. After removal of the acetic acid, the reaction mixture was then partitioned between water and chloroform. Powdered K2CO3 was added and the pH of the aqueous layer was adjusted to 8. After separation, the organic layer was then washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give the crude title compound of 9A as a brown oil (7.81 9), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Reaction time: 2 h
Yield: 91.4 %

Procedure:
3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)benzenamine (800 mg, 3.06 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and methanesulfonyl chloride (0.27 mL, 3.37 mmol) and triethylamine (0.85 mL, 6.13 mmol) were added. The mixture solution was stirred for 2 hours, diluted with ethyl acetate, and then washed with brine. The organic layer was concentrated by drying with magnesium sulfate. Purification by chromatography (10% ethyl acetate/hexane) yielded the target compound (950 mg, 91% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>C1COCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:21])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:7]2[OH:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of methyl 5-bromo-2-(2-phenylacetamido)benzoate (7.71 g, 22.1 mmol, Intermediate 1, step a) in THF (50 mL) at −78° C. was added 1.0 M lithium bis(trimethylsilyl)amide in hexane (48.7 mL, 48.7 mmol) slowly, and the color changed from clear to clear red. The mixture was stirred at −78° C. to room temperature for 4 hours, during which time the color changed to cloudy yellow. The reaction was quenched with water, and acidified with 37% HCl until pH ˜5. The precipitated solid was filtered, washed with water and Et2O, and air dried to give the title compound. More solid was precipitated from the filtrate after standing overnight. The solid was collected by filtering, washing with water and Et2O, and air drying to afford more title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1CCCCC1.C(OCC)(=O)C>[CH3:3][N:5]([CH2:11][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4])[CH3:6]
Reactant: Cc1scc2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: C1CCNCC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1scc2c1N(C(=O)CN1CCCCC1CN(C)C)c1ccccc1NC2=O

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-(dimethylamino)methyl]piperidine to give colorless crystals, mp. 172°-173° C. (cyclohexane/ethyl acetate 4:1 v/v).
Reaction SMILES: [OH:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21].[CH2:27](N1C(=O)CC(=O)N(CC2C=CC=CC=2)C1=O)CCC.C(N(C(C)C)CC)(C)C.N(CC(OCC)=O)=C=O>C(Cl)(Cl)Cl>[CH2:8]([N:7]1[C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:11])[CH2:9][CH2:10][CH3:27]
Reactant: CCCCN1C(=O)CC(=O)N(Cc2ccccc2)C1=O
Reactant: CCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Agent: CCOC(=O)CN=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Reaction time: 3 h
Yield: 63 %

Procedure:
N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A solution of 1-butyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (676 mg, 2.46 mmoles) and diisopropylethylamine (826 uL, 4.93 mmoles) in chloroform (12 mL) was treated with ethyl isocyanatoacetate (211 uL, 2.46 mmoles) and stirred for 3 hours under argon. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was dissolved in ethanol (10 mL), treated with 1 molar sodium hydroxide solution (7 mL) and stirred overnight. The mixture was acidified and extracted into ethyl acetate and the organic solution dried and evaporated. Crystallization from ethanol-water gave the title compound (580 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (s, 1 H), 10.11 (s, 1 H), 7.24-7.35 (m, 5 H), 5.01 (s, 2 H), 4.13 (d, J=5.81 Hz, 2 H), 3.79-3.87 (m, 2 H), 1.54 (dq, J=7.58, 7.41 Hz, 2 H), 1.29 (dq, J=14.97, 7.39 Hz, 2 H), 0.89 (t, J=7.45 Hz, 3 H).