Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[Se:6])([CH3:3])[CH3:2].Cl[CH2:12][C:13](Cl)=[O:14].N1C=CC=CC=1>O1CCCC1>[CH:1]([N:4]1[C:13](=[O:14])[CH2:12][Se:6][C:5]1=[N:7][CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=[Se])NC(C)C
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)N=C1[Se]CC(=O)N1C(C)C
Yield: 101.1 %

Procedure:
0.42 g (2.0 mmol) of N,N′-diisopropyl selenourea were dissolved in 20 mL of tetrahydrofuran. 0.08 mL (1.0 mmol) of chloroacetyl chloride were added to the solution, and after stirring well, the mixture was allowed to react at 0 degrees Celsius for one hour. 0.09 mL (1.0 mmol) of pyridine was then added to the reaction mixture, followed by stirring at 0 degrees Celsius for additional 2 hours. The reaction mixture was extracted by an ordinary method, washed with water and dried, and the solvent was distilled off. As a result, 0.25 g of 3-isopropyl-2-isopropylimino-1,3-selenazolidin-4-one were obtained. The purity was 98.7%, and the yield was 100%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19].O>CCCCCC>[CH3:10][CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: OCc1ccc(O)cc1
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCCCCCC(=O)OCc1ccc(O)cc1
Temperature: 50 °C
Yield: 67.2 %

Procedure:
4-Hydroxybenzyl alcohol (651 mg, 5.24 mmol), 8-methylnonanoic acid (948 mg, 5.50 mmol) and Novozyme 435 (50 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 4-hydroxybenzyl 8-methylnonanoate (0.98 g, yield 67.3%) as a thin-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:29]([NH:28][C:24]3[CH:23]=[C:22]([CH3:21])[CH:27]=[CH:26][CH:25]=3)=[S:30])[CH:3]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1N
Product: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1NC(=S)Nc1cccc(C)c1
Yield: 48.6 %

Procedure:
Prepared according to the procedure described for Example 102 using 3-amino-N-(3,5-dimethylphenyl)-4-methoxy-benzamide from Example 11 (0.542 g, 2.01 mmol) and 3-methylphenyl isothiocyanate (0.28 mL, 2.07 mmol) to afford the product (0.41 g); m.p. 188-189° C.
Reaction SMILES: [OH-].[Na+].O.[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]=1[OH:18])([CH3:7])([CH3:6])[CH3:5].[CH2:19](Br)[CH:20]=[CH2:21]>C1(C)C=CC=CC=1>[C:14]([C:10]1[CH:11]=[C:12]([CH2:21][CH:20]=[CH2:19])[CH:13]=[C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[C:9]=1[OH:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCBr
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A 1 liter, 3 neck flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, dropping funnel and condenser was charged with 40 grams (1.0 mole) of sodium hydroxide and 50 ml. of H2O. The NaOH was dissolved with stirring and the solution was cooled to 25° C. and then 100 ml. of toluene, 2.06 grams (0.01 moles) 2,6-di-t-butyl phenol and 6.25 grams (≈0.006 moles) of S-X1 polystyrene quaternary phosphonium resin catalyst was charged into the reaction vessel. The dropping funnel was charged with a solution prepared from 49.44 grams (0.264 mole) of 2,6-di-t-butyl phenol, 32.0 grams (0.264 mole) of allyl bromide and 100 ml. of toluene. This solution was then added dropwise over a 40 minute period to the reaction vessel which had been heated to 50°-60° C. as stirring took place under a nitrogen blanket. After 3 hours of reaction time at 72° C. gas chromatographic analysis indicated that 50% of the starting materials had reacted to form 2,6-di-t-butyl-4-allyl phenol.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])C.[CH3:21][NH2:22]>C(O)C>[CH3:21][N:22]1[C:7]2([OH:18])[C:6]([CH3:19])([C:15]3[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8]2)[CH2:5][C:4]1=[O:3]
Reactant: CN
Reactant: CCOC(=O)CC1(C)C(=O)CCc2ccc(OC)cc21
Solvent: CCO
Product: COc1ccc2c(c1)C1(C)CC(=O)N(C)C1(O)CC2

Procedure:
The solution of 22.0 g (79.7 mmol) ethyl-7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate (IXb) and 7.5 g (240 mmol) methylamine in 25 ml ethanol was left at room temperature for 24 hr. The crystalline precipitate formed was separated to give 15.5 g (74.5%) Xb, m.p. 182°-186°. From the mother liquor, after evaporation (35°) and treatment with ether, 1.0 g, additional Xb was collected increasing the yield to 79.5%; IR (Nujol), 3300 (OH), 1670 cm-1 (lactam); NMR (CDCl3 -DMSO) δ, 1.48 (s, 3, CH3), 2.82 (s, 3, N--CH3), 3.78 (s, 3, OCH3), 6.6-7.1 (m, 3, ArH).
Reaction SMILES: [F:1][C:2]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15]([O:17]CC)=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1.O.[OH-].[Li+]>O1CCCC1.O>[F:26][C:2]([F:1])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1
Reactant: CCOC(=O)c1sc(-c2cn(CC(F)(F)c3ccccc3)nn2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn(CC(F)(F)c3ccccc3)nn2)sc1C(=O)O
Yield: 84 %

Procedure:
To a solution of ethyl 2-(1-(2,2-difluoro-2-phenylethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate (0.13 g, 0.34 mmol) in a mixture of tetrahydrofuran (8 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.05 g, 1.24 mmol). The reaction mixture was heated to reflux for 17 hours. The solvent was removed in vacuo, and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford the title compound as a white solid (0.10 g, 84%): MS (ES+) m/z 349.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].CC(C)([O-])C.[Li+].Cl[CH2:28][C:29]1[C:37]2[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:35][CH:36]=2)[N:31]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:30]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:28][C:29]4[C:37]5[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]6[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=6)=[CH:35][CH:36]=5)[N:31]([CH2:48][C:49]5[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=5)[N:30]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(Cn4nnc5c(Oc6cc(Cl)cc(C#N)c6)c(Cl)ccc54)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (140 mg, 0.459 mmol) and lithium tert-butoxide (37 mg, 0.459 mmol) were dissolved in DMF (1 mL) under N2 and allowed to stir for 20 minutes. After this time, the reaction was cooled to 0° C. and 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-6-amine as a solution in DMF (1 mL) was added dropwise. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (3 mL), diluted with water (3 mL) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic fractions were washed with dilute brine (4×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (12 g), eluting with 0-100% EtOAc/hexanes to give the title compound. LRMS (M+1)=690.5.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:32]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:22]1[CH:21]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: Fc1ccccc1-c1ccccc1
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2ccccc2-c2ccccc2)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 2-fluoro-biphenyl were converted to yield Allyl-[5-(1-biphenyl-2-yl-1H-indol-5-yl)-pentyl]-methyl-amine as light yellow oil, MS: 409 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:15]=[C:14](/[CH:25]=[N:26]/[OH:27])[CH:13]=2)[CH3:9])=[N:6][CH:7]=1.[Cl:29]N1C(=O)CCC1=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11]([C:12]2[CH:13]=[C:14]([C:25]([Cl:29])=[N:26][OH:27])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)=[O:28])[CH3:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-c2cc(/C=N/O)cc(C(=O)N[C@H](C)c3ccc(F)cn3)c2)nc1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)cn3)cc(C(Cl)=NO)c2)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of N-[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]-3-[(E)-(hydroxyimino)methyl]-5-(5-methyl-2-pyridinyl)benzamide (0.703 g, 1.86 mmol) N,N-dimethylformamide (1.9 mL) was added N-chlorosuccinimide (0.260 g, 1.95 mmol). The reaction mixture was stirred at 50° C. for 1 h. The temperature was raised to 70° C. for 1 h. The mixture was cooled to ambient temperature. Water was added. The mixture was extracted with diethyl ether (3×). The combined organic extracts were washed with water (3×), dried over magnesium sulfate, filtered and concentrated to give the title compound (0.795 g) MS 413.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])[N:3]=1.[Cl:24][C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>N1C=CC=CC=1.ClCCl.CO.CS(C)=O>[Cl:24][C:25]1[S:29][C:28]([S:30]([NH:1][C:2]2[C:10]3[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH2:20])=[O:19])[N:3]=2)(=[O:32])=[O:31])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1ccc(F)c2c1c(N)nn2Cc1cccc(C(N)=O)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45 %

Procedure:
To a solution of 3-{[3-amino-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Intermediate 14) (22 mg, 0.07 mmol) in anhydrous pyridine (1 mL) and anhydrous dichloromethane (3 mL) (gentle heating of the mixture for a few minutes with a heatgun was required in order for the starting material to go in solution) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (16.71 mg, 0.077 mmol) in anhydrous dichloromethane (0.5 mL). The reaction was stirred at room temperature for 45 min, then at 45° C. for 30 min. A solution of 5-chloro-2-thiophenesulfonyl chloride (16.7 mg) in anhydrous dichloromethane (0.2 mL) was added to the reaction mixture and stirred at 45° C. for 25 h. The reaction mixture was cooled and then partitioned between water and dichloromethane. The organic layer was passed through an hydrophobic frit and evaporated in-vacuo to yield a pale yellow solid. The solid was dissolved in MeOH-DMSO (1 mL) and purified by MDAP on Sunfire C18 column, eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile). Appropriate fraction was evaporated in-vacuo to yield the title compound as a white solid (15.7 mg, 45%). LCMS (5 min run) RT=2.62 min, ES+ve m/z 495/497 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[Cl:13])=[C:4]([NH:11][CH3:12])[N:3]=1
Reactant: CNc1nc(Cl)nc2[nH]cnc12
Reactant: ClCc1ccccc1Cl
Product: CNc1nc(Cl)nc2c1ncn2Cc1ccccc1Cl

Procedure:
In a manner analogous to that described in Example 17 it is possible, by reacting 2-chloro-6-(N-methylamino)-9H-purine (Example 6) with 2-chlorobenzyl chloride, to obtain the 2-chloro-9-(2-chlorobenzyl)-6-(N-methylamino)-9H-purine, which melts at from 203° to 204° (N,N-dimethylformamide/diethyl ether).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:15])[CH:11]=[C:12]([CH3:14])[CH3:13]>O=[Mn]=O.CCCCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CC(O)C1=C(C)CCCC1(C)C
Agent: O=[Mn]=O
Solvent: CCCCC
Product: CC(C)=CC(=O)C1=C(C)CCCC1(C)C
Yield: 63 %

Procedure:
2,6,6-Trimethyl-1[1-hydroxy-3-methyl-2-butenyl]-1-cyclohexene, prepared according to Example 6, (1.0 g.) with activated MnO2 (10 g.) in 30 ml. of pentane was mixed at room temperature during 63 h. after filtration and distillation 630 mg. (63 %) of the desired ketone, B.p. 67°/0.001 Torr, were obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:17]3[CH2:20][CH2:19][CH2:18]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.ClC1C(C(NC(C2CCC2)=O)C2C=CC=CC=2)=[N:24]C=CN=1.O=P(Cl)(Cl)Cl>>[CH:17]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:24])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nccn2c(C3CCC3)nc(-c3ccccc3)c12
Reactant: O=C(NC(c1ccccc1)c1nccnc1Cl)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nccn2c(C3CCC3)nc(-c3ccccc3)c12
Temperature: 55 °C
Yield: 90 %

Procedure:
8-Chloro-3-cyclobutyl-1-phenylimidazo[1,5-a]pyrazine: A mixture of cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-phenylmethyl]-amide (710 mg, 2.35 mmol) and POCl3 (15 mL, 25 g, 163 mmol) was heated to 55° C., under N2 atmosphere, for 21 h. POCl3 was evaporated in vacuo, a cold solution of NH3 in i-PrOH (2M, 15 mL) was added until pH was basic, and rotary evaporation was used to remove excess solvent. The crude material was suspended between EtOAc and dH2O, the layers were separated, and the aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with NaHCO3 sat. aq. sol. (2×50 mL) and brine (1×50 mL), dried over anhydrous MgSO4, and filtered. Sample was purified by filtration through a silica gel plug with 10% EtOAc:CH2Cl2 (250 mL) and filtrate was concentrated in vacuo, affording 602.9 mg (90%, 2.125 mmol) of the title compound, containing ≈0.5 equivalents of reduced DIAD and ≦0.06 equivalents of cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-phenylmethyl]-amide (4), as a gold-colored solid; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.11 (m, 1H), 2.13-2.26 (m, 1H), 2.47-2.57 (m, 2H), 2.60-2.72 (m, 2H), 3.85 (quint, J=8.4 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 7.38-7.47 (m, 3H), 7.50 (d, J=5.2 Hz, 1H), 7.67-7.71 (m, 2H). MS (ES+): m/z 284.1/286.1 (100/55) [MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (110 mg, 1.17 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(3-chlorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 22; 200 mg, 0.59 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.70 mmol) and 1-Hydroxybenzotriazole (95 mg, 0.70 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 70 mg.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([CH3:16])([CH3:15])[C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[Cl:10]>CCOCC>[Br:1][CH2:13][C:12](=[O:14])[C:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)([CH3:16])[CH3:15]
Reactant: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Reactant: BrBr
Solvent: CCOCC
Product: CC(C)(C(=O)CBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (1.84 ml) in ether (25 ml) was added dropwise over 1 hour at ambient temperature to a stirred solution of 3-(3,4-dichlorophenyl)-3-methylbutan-2-one (8.24 g) in ether (250 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 30 minutes then it was washed with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried (MgSO4), and the solvent removed in vacuo to give 1-bromo-3-(3,4-dichlorophenyl)-3 methylbutan-2-one as an oil (9.57 g) which was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1ccc(SC)cc1O
Product: COC(=O)c1ccc(SC)cc1OCCNC(=O)OC(C)(C)C

Procedure:
Methyl 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoate was prepared (12.6 g, 76%) as described in Example 21-C from methyl 2-hyroxy-4-(methylthio)benzoate and 2-(tert-butoxycarbonylamino)ethanol.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH:18][C:19]1[NH:23][C:22]2[C:24]3[CH2:25][C:26]([CH3:36])([CH3:35])[O:27][C:28]=3[C:29]([C:31](OC)=O)=[CH:30][C:21]=2[N:20]=1>C1COCC1.O>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH:18][C:19]1[NH:23][C:22]2[C:24]3[CH2:25][C:26]([CH3:36])([CH3:35])[O:27][C:28]=3[C:29]([C:31]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)=[CH:30][C:21]=2[N:20]=1
Reactant: CC(C)C(N)=NO
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1noc(-c2cc3nc(Nc4c(F)cccc4Cl)[nH]c3c3c2OC(C)(C)C3)n1
Yield: 17.7 %

Procedure:
Under nitrogen atmosphere, to a solution of N′-hydroxyisobutyrimidamide (0.028 g, 0.268 mmol) in THF was added sodium hydride (0.021 g, 0.51 mmol). The reaction mass was refluxed for 15-20 minutes. Then added methyl 2-((2-chloro-6-fluorophenyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.255 mmol) and continued reflux for 4-5 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified column chromatography to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.28 (d, 6H), 1.48 (s, 6H), 3.09 (m, 3H), 7.24 (m, 1H), 7.39 (m, 1H), 7.54 (d, J=7.2 Hz, 1H), 9-10 (s, 1H), 10.5 (s, 1H); MS [M]+: 458.14.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccccc3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and phenyl boronic acid according to the procedure described in example 21. MS m/z 237; HRMS: calcd for C17H16O+H+, 237.12739; found (ESI, [M+H]+), 237.1271.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:19])(=[O:30])=[O:29])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: Cc1cc(C)c(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)c(C)c1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2,4,6-trimethylbenzenesulfonylchloride, the title compound was obtained in a similar yield: mp 171°-172° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 7.94 (s, 1H, CH=N), 7.80 (s, 1H, CH=N), 7.68 (s, 4H, arom), 7.7-7.0 (m, 3H, arom), 6.88 (s, 2H, arom), 4.93 (AB system, Δv=0.32, J=14.5 Hz, 2H, CH2 -Tr), 3.7-3.3 (m, 2H, CH2NH), 2.54 (s, 6H, 2Me), 2.29 (s, 3H, Me). Anal calcd. for C20H22Cl2N4O3S: C 51.18%; H 4.72%; N 11.94%. Found: C 51.26%; H 4.98%; N 11.92%.