Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](OC(=O)C)=[O:2].C(O)=O.C(OC(=O)C)(=O)C.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[CH:29]([S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][NH2:31]>C1COCC1>[C:33]1([S:32][CH:29]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:27]=[CH:28][C:19]=2[O:18][CH3:17])[CH2:30][NH:31][CH:1]=[O:2])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)OC=O
Reactant: COc1ccc2ccccc2c1C(CN)Sc1ccccc1
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2ccccc2c1C(CNC=O)Sc1ccccc1
Temperature: 0 °C
Yield: 85 %

Procedure:
Acetic formic anhydride is generated by dropwise addition of 98% formic acid (1472 mg, 32 mmol) to 2655 mg (26 mmol) of acetic anhydride maintained at 0° C. followed by gentle heating at 50°-60° C. for 2 h. The mixture is cooled to -15° C. and 20 ml of THF are added. To the resulting solution is added dropwise at -15° C. a solution of 1-(2-methoxynaphth-1-yl)-1-(phenylthio)-2-aminoethane (3094 mg, 10 mmol) in THF (50 ml). The reaction mixture is allowed to warm to room temperature and the volatiles are removed in vacuo. The residue is taken up in ether. The ether solution is washed with water and NaHCO3 solution, dried over anhydrous K2CO3 and then evaporated in vacuo. The oily residue is triturated with ethyl acetate-hexane mixture to give crystalline title compound in 85% yield (2870 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[NH:37][C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[N:37]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1NC(=O)N(COCc2ccccc2)C1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(COCc4ccccc4)C(=O)C3C)nc2)CC1
Yield: 88.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (321 mg) described in Preparation Example 144 and 3-benzyloxymethyl-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 206 and by the reaction and treatment in the same manner as in Example 536, the title compound (391 mg) was obtained.
Reaction SMILES: [CH2:1]([CH:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].C(C(C(=O)C)C(OCC)=O)C>>[CH2:1]([CH:3]([CH:8]([OH:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: CCC(C(C)=O)C(=O)OC
Agent: CCOC(=O)C(CC)C(C)=O
Product: CCC(C(=O)OC)C(C)O
Yield: 50 %

Procedure:
Methyl 2-ethyl-3-hydroxybutyrate was prepared following the procedure as described in step 2) of Preparation Example 4, except for that methyl 2-ethyl-3-oxo-butyrate was used to replace for ethyl 2-ethyl-3-oxo-butyrate. Yield 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[F:15][C:16]([F:38])([F:37])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH:20]=[CH:21][CH:22]=1>>[F:38][C:16]([F:15])([F:37])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Si:33]([CH3:35])([CH3:34])[CH3:36])=[CH:29][CH:28]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: C[Si](C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Product: C[Si](C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [2-(3-trifluoromethyl-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [2-(3-trifluoromethyl-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine. MS (ISP) 547.3/549.4 (100/33) (M+H)+.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([CH2:35]O)[CH:24]=1>C(Cl)(Cl)Cl>[Br:1][CH2:35][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCc1cc(F)ccc1-c1ccccc1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2ccccc2)c(CBr)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine dibromide (35.5 g, 2 eq) was added in one portion to a solution of (4-fluoro-[1,1′-biphenyl]-2-yl)methanol (8.5 g, 42 mmol) in chloroform (250 mL). The reaction mixture was heated at 60° C. and left to stir overnight. The solid was filtered off and the solvent removed in vacuo. The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (0:100 to 30:70), to give the title compound as an oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1([CH2:34][OH:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:26][CH2:27][C:28]3([CH2:34][OH:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCC1(CO)CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3(CO)CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and [4-(aminomethyl)tetrahydro-2H-pyran-4-yl]methanol and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][N:27]([C:22]4[N:21]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:28][CH2:29]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cnc(N2CCN(CCCOc3ccc(-c4csc5ccccc45)cc3)CC2)nc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 1-(2-pyrimidyl)piperazine, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=99%, [M+H]+=431.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[CH:31]=1)=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:26][O:27][C:28](=[O:29])[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:14])([F:15])[F:16])=[C:2]([Cl:1])[CH:3]=2)[CH:31]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccnc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3) was reacted with methyl-2-aminopyridin-4-carboxylate and HBTU at 80° C. for 5 h to give the title compound as white solid. MS (m/e)=528.3 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4]Cl.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21][CH2:4][C:3]=2[CH:6]=1
Reactant: Oc1ccccc1S
Reactant: FC(F)(F)c1ccc(Cl)c(CCl)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(c1)CSc1ccccc1O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A solution of 45 g of 2-chloro-5-trifluoromethylbenzyl chloride (B. Pecherer, U.S. Pat. No. 3,465,051; Chem.Abstr. 71, 123 885, 1969) and 37.6 g of 2-hydroxythiophenol (cf.Example 18, reference given) in 800 ml of dimethylformamide is treated with 27.2 g of potassium carbonate and the mixture stirred for 3 hours in a nitrogen atmosphere at a room temperature. Further 30 g of potassium carbonate and 3 g of copper are then added and the mixture refluxed for 12 hours. Dimethylformamide is distilled off in vacuo and the residue separated between water and benzene. It is then filtered, the benzene layer of the filtrate separated, dried with potassium carbonate and processed by distillation. There are obtained 40.2 g of (73%) 2-trifluoromethyl-11H-dibenz (b,f)-1,4-oxathiepin boiling at 135°-137° C./0.1 kPa. The distillate crystallizes from petroleum ether and the pure 1,4-oxathiepin (cf. Example 16) in 30 ml of benzene was added dropwise for 1 hour to a refluxing solution of 3.9 g of ethyl chloroformate in 15 ml of benzene. The mixture was refluxed for 1.5 hours and, after cooling washed with water, with 10% sulfuric acid and again with water. It was then dried with magnesium sulfate and evaporated. The residue (the crude carbamate) was dissolved in 10 ml of ethanol and the solution treated with 9.0 g of potassium hydroxide. Then, the mixture was refluxed for 2 hours in a bath having a temperature of 130° C. It was diluted with water and extracted with benzene. From the benzene solution the basic product was reextracted by shaking with excessive 10% hydrochloric acid. The aqueous layer together with the oily hydrochloride were separated, made alkaline with aqueous ammonia and the released base extracted with benzene. The extract was dried with potassium carbonate and evaporated. There were obtained 4.0 g of an oily base which was neutralized with 1.9 g of oxalic acid in acetone. The hydrogen oxalate crystallized in a yield of 5.15 g was recrystallized from aqueous ethanol and melted at 210°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[O:20])[C:17](Cl)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1>COCCOC>[S:25]1[CH:26]=[N:27][N:28]=[C:24]1[NH:23][C:17](=[O:18])[C:16]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH:8]=1)=[O:20]
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccccc12
Reactant: Nc1nncs1
Solvent: COCCOC
Product: O=C(Nc1nncs1)C(=O)c1cn(Cc2ccc(F)cc2)c2ccccc12
Reaction time: 12 h
Yield: 49.1 %

Procedure:
A solution of 2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (318 mg) in dry 1,2-dimethoxyethane (5 ml) is added dropwise to a suspension of 2-amino-1,3,4-thiadiazole (91 mg) and dry, ground K2CO3 (138 mg) in 5 ml of 1,2-dimethoxyethane, operating at room temperature. The reaction mixture is left under stirring for 12 hours then poured into water (60 ml). The resulting suspension is stirred for 30 minutes. The precipitate is filtered off and suspended in methanol (10 ml) under stirring for 30 minutes. The solid is recovered by filtration and dried to give N-(1,3,4-thiadiazol-2-yl)-2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide (168 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[S:16](=[O:26])(=[O:25])[CH2:15][CH2:14]2)[CH:3]=1.CC1(C)[O:32][CH:31]([CH2:33][NH2:34])[CH2:30][O:29]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[S:16](=[O:25])(=[O:26])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:34][CH2:33][CH:31]([OH:32])[CH2:30][OH:29]
Reactant: CC1(C)OCC(CN)O1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3C)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3C)cc(NCC(O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 32-1 in Scheme 10 by using 4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (dd, J=7.96, 1.39 Hz, 1 H), 7.90 (d, J=6.57 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.46 (ddd, J=8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J=8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d, J=6.82 Hz, 1 H), 4.64-4.53 (m, 4 H), 3.70 (d, J=8.59 Hz, 1 H), 3.62-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d, J=7.07 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc(Br)c(C)cc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Bromo-2-methoxy-5-methyl-phenol (see Chien-Hsun et al., Syn. Lett., 12, 1351–1352 (1997)) was stirred in dry CH2Cl2 (100 mL) at 23° C. DIEA (6.05 mL, 34.6 mmol), and then 2-(trimethylsilyl)ethoxymethyl chloride (5.6 mL, 31.7 mmol) were added. After stirring for 1 h, the solution was washed with H2O, 0.1 N HCl, H2O, saturated NaHCO3, and brine (25 mL each). Organics were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (6% ethyl acetate/hexanes) gave 9.06 g (91%) of [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.06 (s, 1 H), 7.02 (s, 1 H), 5.24 (s, 2 H), 3.84 (s, 3 H), 3.79 (t, 2 H, J=8.4 Hz), 2.31 (s, 3 H), 0.96 (t, 2 H, J=8.4 Hz), 0.01 (s, 9 H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:17]=[CH:16][C:5]3[N:6]([C:15]4[CH:16]=[CH:17][CH:2]=[CH:3][CH:4]=4)[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cn1c(-c2ccccc2)nc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2ccc3c(c2)nc(-c2ccccc2)n3-c2ccccc2)cc1
Yield: 145.9 %

Procedure:
2.0 g (7.2 mmol) of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole, 1.2 g (7.9 mmol) of 4-chlorophenylboronic acid, and 0.17 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the resultant had been stood to cool, an aqueous layer was removed and an organic layer was dried with magnesium sulfate. After the solvent had been distilled off under reduced pressure, the resultant solid was purified by means of silica gel column chromatography to obtain 2.0 g of 5-(4-chlorophenyl)-1,2-diphenyl-1H-benzimidazole (87% yield).
Reaction SMILES: C([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][N:25]=2)[CH2:10]1)C1C=CC=CC=1.ClB(Cl)Cl>C(Cl)Cl>[Cl:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]([O:23][C@H:11]2[CH2:10][C@H:9]([OH:8])[C@H:13]([CH2:14][OH:15])[CH2:12]2)[CH:29]=1
Reactant: Clc1cc(O[C@@H]2C[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)C2)ncn1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
The crude intermediate 4-((1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentyloxy)-6-chloropyrimidine (25) was taken up in methylene chloride (3000 mL) and the mixture was cooled to 0° C. 1.0 M of Trichloro-borane in methylene chloride (1087.538 mL, 1087.538 mmol) was added slowly maintaining <10° C. The resulting mixture was allowed to stir for 1 hour at 0° C. HPLC analysis indicated consumption of starting material. The reaction mixture was added slowly to saturated sodium bicarbonate in water (2300 mL) and the biphasic mixture was allowed to stir for 20 minutes. The methylene chloride layer was separated and the aqueous extracted twice with methylene chloride (2300 mL). The organics were combined and concentrated. The residue was purified by eluting through a silica gel (1 kg) plug with 50 to 100% ethyl acetate/hexane (hexane (6 L)+ethyl acetate (14 L). The desired fractions were combined and concentrated to give a red solid (124 g, 70%). 1H NMR (300 MHz, CD3OD, δ): 8.58 (s, 1H), 6.91 (s, 1H), 5.61 (m, 1H), 4.39 (t, 1H), 3.75 (m, 1H), 3.61 (m, 1H), 2.25 (m, 3H) and 2.00 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.C(#N)C.Cl[C:18]1[N:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:18]2[N:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: Cc1ccc(O)c2c1OCC21CC1
Solvent: CC#N
Product: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC21CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 13, 176 mg, 1 mmol) in dry Acetonitrile (4 ml) potassium carbonate (207 mg, 1.5 mmol) and then 2-chloro-5-nitropyrimidine (159 mg, 1 mmol) were added and the reaction mixture was stirred for 24 hours at 80° C. After cooling the reaction mixture was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated affording the title compound (258 mg) as an orange solid that was used in the next step as crude material without further purification.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:33])[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]>CO.C1COCC1>[OH:31][CH:29]([CH3:30])[CH2:28][CH2:27][C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH:4]([OH:3])[CH3:33])=[CH:15][CH:14]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1)=[O:32]
Reactant: CC(=O)CCC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)CCC(C)=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)CCC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)CCC(C)O)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of sodium borohydride in methanol was cooled to 5° C. A solution of 4-oxo-pentanoic acid {4-[4-(4-oxo-pentanoylamino)-benzenesulfonyl]-phenyl}-amide in THF was added and the resulting reaction mixture was stirred at room temperature. After workup and purification, the product was obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([C:11]1[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[O:20][CH3:21])=[N:6]2.[OH-:22].[K+]>>[Br:17][C:15]1[C:14]([O:18][CH3:19])=[CH:13][C:12]([O:20][CH3:21])=[C:11]([C:5]2[N:4]=[C:3]3[C:7](=[N:8][CH:9]=[N:10][C:2]3=[O:22])[N:6]=2)[CH:16]=1
Reactant: COc1cc(OC)c(-c2nc3ncnc(Cl)c3[nH]2)cc1Br
Reactant: [OH-]
Agent: [K+]
Product: COc1cc(OC)c(C2=NC3=NC=NC(=O)C3=N2)cc1Br

Procedure:
Prepared analogously to Example 16 from 6-chloro-8-(5-bromo-2,4-dimethoxy-phenyl)-purine by reaction with 20% potassium hydroxide solution.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.CS(C)=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (805.4 g), 2-methylimidazole (1101.7 g) and dimethyl sulfoxide (2416 mL) was stirred at 110° C. for 8 h and water was added to the obtained mixture. The mixture was extracted with ethyl acetate and the extract was washed with 5% brine. The solvent was evaporated and the residue was dissolved in ethyl acetate (1611 mL) with heating. n-Heptane (4832 mL) was added at 30° C. The precipitated crystals were collected by filtration and washed with ethyl acetate-n-heptane (1:3) to give the title compound (716.6 g, yield: 77.2%).
Reaction SMILES: [NH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[NH2:2].C(O)(=O)C.CN(C)/[CH:20]=[CH:21]/[C:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])=O>C(O)C>[OH:34][C:25]1[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=1[C:22]1[N:1]([CH:3]2[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]2)[N:2]=[CH:20][CH:21]=1
Reactant: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of crude tert-butyl 3-hydrazinoazetidine-1-carboxylate, (Preparation 696, 5.7 g, 0.030 mol) in ethanol (66 mL) at 0° C. was added acetic acid (6.6 mL) dropwise. Then (2E)-3-(dimethylamino)-1-[2-hydroxy-5-(trifluoromethyl)phenyl]prop-2-en-1-one, (Preparation 859, 6.4 g, 24.68 m mol) was added portionwise and allowed to stir at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and neutralised with aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate (150 mL). The combined organic layer was washed with water (100 mL), saturated aqueous sodium chloride solution (50 mL) and dried over anhydrous sodium sulphate. After concentration of organic layer in vacuo, the crude product was washed with 20% v/v ethyl acetate in hexane to get the title compound as a white solid (7.4 g)