Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([N:12](CC)[CH2:13][CH3:14])[CH3:11].C(NCC)C>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: BrCc1ccc(Br)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and diethylamine (0.84 mL, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.85 g, 88%). 1H NMR (CDCl3, 300 MHz): 7.45-7.38 (m, 2H), 7.27-7.18 (m, 2H), 3.50 (s, 2H), 2.50 (q, J=7.1 Hz, 4H), 1.03 (t, J=7.1 Hz, 6H). LCMS (Method G): RT=1.98 min, M−H+=242.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH2:22][OH:23])=[O:19])=[O:12].CN(C)C>CS(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=[O:23])=[O:19])=[O:12]
Reactant: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1CO
Agent: CN(C)C
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)[C@H]1NCSC1C(=O)CC1Cc2ccccc2C1
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinol (590 mg) and trimethylamine (1.32 ml) were dissolved in 1.50 ml of dimethyl sulfoxide, followed by addition of 1.55 g of sulfur trioxide-pyridine complex dissolved in 2.25 ml of dimethyl sulfoxide at room temperature under agitation, which was then agitated for 15 minutes. The reaction solution was placed in ice-cold water, followed by extraction with chloroform. The organic phase was washed sequentially in 5% HCl, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography, to obtain 107 mg of 1-[3-(indan-2-yl acetyl)-L-thioprolyl]-L-prolinal. Yield; 18%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[C:14]([NH:17][CH:18]([CH3:20])[CH3:19])[O:15][CH:16]=1)[CH:8]=[C:7]2[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][O:38][C:39]([C:41]1([NH:46][C:47]([CH:49]2[CH2:53][CH:52](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:51][N:50]2[C:65](=[O:79])[CH:66]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:67]([CH3:70])([CH3:69])[CH3:68])=[O:48])[CH2:43][CH:42]1[CH:44]=[CH2:45])=[O:40].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.CCOC(C)=O.[Cl-].[Li+].CO>[CH3:37][O:38][C:39]([C:41]1([NH:46][C:47]([CH:49]2[CH2:53][CH:52]([O:21][C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[C:3]([O:22][CH2:23][CH2:24][N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:4][CH:5]=4)[N:10]=[C:9]([C:12]4[N:13]=[C:14]([NH:17][CH:18]([CH3:19])[CH3:20])[O:15][CH:16]=4)[CH:8]=3)[CH2:51][N:50]2[C:65](=[O:79])[CH:66]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:67]([CH3:70])([CH3:69])[CH3:68])=[O:48])[CH2:43][CH:42]1[CH:44]=[CH2:45])=[O:40]
Reactant: C=CC1CC1(NC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)OC
Reactant: CC(C)Nc1nc(-c2cc(O)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)co1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3coc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)OC
Temperature: 65 °C
Yield: 134.4 %

Procedure:
To a solution of 8-chloro-2-(2-isopropylaminooxazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-ol (341 mg, 0.63 mmol) and cesium carbonate (1.23 g, 3.78 mmol) in NMP was added 1-{[4-(4-bromobenzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid methyl ester (432 mg, 0.63 mmol) and the reaction was heated to 65° C. After 2 h an additional 0.5 eq of 1-{[4-(4-bromo-benzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid methyl ester was added and stirred an additional hour. The reaction was diluted with EtOAc and 5% lithium chloride with stirring. The reaction was transferred to a separatory funnel and saturated sodium bicarbonate and MeOH (2 ml) was added. The layers were separated and the aqueous extracted again with EtOAc. The combined organic layers were then washed with 5% lithium chloride, dried over magnesium sulfated and concentrated to give 747 mg (99% yield) of 1-({1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-4-[8-chloro-2-(2-isopropylaminooxazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-vinyl-cyclopropanecarboxylic acid methyl ester as a yellow oil. LCMS found 882.11 [M+H]+.
Reaction SMILES: I.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[NH:17])[NH2:16])[CH2:11][CH2:10]1)=[O:8].C(N1CCN(C2N=[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=[C:35]3N=2)CC1)(=O)C1C=CC=CC=1.C1(CN2CCN(C3N=C4C=CC=CC=C4N=3)CC2)C=CC=CC=1.C1(N2CCN(C3N=C4C=CC=CC=C4N=3)CC2)C=CC=CC=1.C(N1CCN(C2N=C3C=CC=CC=C3N=2)CC1)=O>C(OCC)(=O)C.CO>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=[C:35]3[N:17]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(c1ccccc1)N1CCN(c2nc3cccccc-3n2)CC1
Reactant: N=C(N)N1CCN(C(=O)c2ccco2)CC1
Agent: I
Agent: O=CN1CCN(c2nc3cccccc-3n2)CC1
Agent: c1ccc(CN2CCN(c3nc4cccccc-4n3)CC2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(c1ccco1)N1CCN(c2nc3cccccc-3n2)CC1

Procedure:
In the same manner but replacing 4-(2-furanylcarbonyl)-1-piperazinecarboximidamide hydroiodide with an equivalent amount of another compound of formula III, described in Example 12, the following compounds of formula I were obtained, respectively: 2-(4-benzoyl-1-piperazinyl)cycloheptimidazole: (I: R1 is benzoyl) mp 148°-149° C.(ethyl acetate); ir(mull)1623 cm-1 and uv max(MeOH) 289(ε30,340), 263(ε29,700) and 239 nm(ε7,950); 2-[4-(phenylmethyl)-1-piperazinyl]-cycloheptimidazole: (I: R1 is phenylmethyl) mp 97°-99° C.(ethyl acetate); ir(CHCl3) 3660, 3330, 1600, 1565, 1525, 1495 and 697 cm-1 ; uv max (MeOH) 295 (ε6,750), 251(ε26,440) and 238 nm(ε25,860); nmr (CDCl3)δ2.6(4H,t), 3.57(2H,s), 4.05(4H,t) and 7.35-8.15(10H,m) and Anal. Calcd for C19H20N4 : C, 74.90% H, 6.65% N, 18.45% and Found: C, 74.63% H, 6.60% N, 77.65%; 2-(4-phenyl-1-piperazinyl)cycloheptimidazole: (I: R1 is phenyl) mp 210°-212° C. (ethyl acetate); ir(mull) 1595, 1570, 1530 and 1503 cm-1 ; uv max (MeOH) 288(δ7,960), 260(ε34,040) and 241 nm(ε29,530); nmr(CDCl3)δ3.35(4H,t), 4.23(4h,t) and 7.5(10H,m) and Anal. Calcd. for C18H18N4O: C, 74.46% H, 6.25%, N, 19.29% and Found C, 74.12% H, 6.07% N, 19.16%; and 2-(4-formyl-1-piperazinyl)cycloheptimidazole: (I: R1 is formyl) mp 165°-167° C. (ethyl acetate); ir(mull) 1670 cm-1 ; nmr(CDCl3)δ 3.9(8H,m) and 7.9(6H,m) and Anal. Calcd for C13H14N4O: C, 64.43% H, 5.82% N, 23.12% and Found: C, 64.44% H, 5.80% N, 22.66%.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH:27]=[O:28])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH:29]O.Cl>[OH-].[Na+]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]([C:27]([OH:29])=[O:28])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: OO
Reactant: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccc(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
100 mg of compound 2 (0.269 mmol) are dissolved in 50 mL of 0.1 N NaOH and 158 mL (1.6 mmol) of 35% H2O2 are added. The mixture is left to stand at ambient temperature for 18 h. The mixture is cooled to 0° C. and adjusted to pH 2 with 2N HCl. The solid is filtered out and washed with water. Drying is performed in a vacuum oven at 40° C. Product: 54 mg. Formula: C22H21N5O2 (m.w. 387.43). Yield 52%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].C[O:15][P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([P:16](=[O:15])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
20 parts of 2,6-dimethoxybenzoyl chloride are suspended in 20 parts by volume of toluene in the same apparatus as described for the preparation of initiator XX, and 21.6 parts of methoxydiphenylphosphine are added dropwise to this mixture at 50°-55° C., whilst stirring. Stirring is continued for 3 hours at 50° C. and the product is then recrystallized directly from toluene. 32 parts of yellowish crystals are obtained. Melting point: 124°-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:22])=[C:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]([CH3:22])[CH:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)=C(CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)C(CC(C)C)C(=O)O

Procedure:
E and Z benzyl 3-(ethoxycarbonyl)-2-(2-methylpropyl)butenoate (5.0 g.) was hydrogenated at 120 psi at 60° C. in methanol (50 mls.) in the presence of 10% palladium on charcoal (0.25 g.) for 48 hours. The resultant mixture was filtered through Celite and the solvent removed by evaporation in vacuo to yield 3-(ethoxycarbonyl)-2-(2-methylpropyl)butanoic acid as a mixture of isomers in the form of a thick oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@@H:21]([OH:23])[CH3:22])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@@H:21]([OH:23])[CH3:22])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: OB(O)c1ccccc1F
Reactant: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccccc3F)ccc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
A mixture of (1S)-1-{2-[(6-bromo-2-naphthyl)sulfonyl]phenyl}ethanol [Example 10 Step 2] (102 mg, 0.26 mmol), 2-fluorophenylboronic acid (75 mg, 0.53 mmol), palladium(II) acetate (3 mg, 0.013 mmol), tri(o-tolyl)phosphine (9 mg, 0.028 mmol), sodium carbonate (83 mg, 0.787 mmol) and water (0.5 mL) in 1,2-dimethoxyethane (3 mL) was degassed and stirred at 80° C. (oil bath temperature) under nitrogen for 16 hours. The cooled reaction mixture was diluted with ethyl acetate and filtered. The filtrate was evaporated and the residue purified by flash chromatography, eluting with 60-75% diethyl ether/isohexane, to afford the title compound as a foam (86 mg, 81%). 1H NMR (500 MHz, CDCl3) δ 8.56 (1H, s), 8.17 (1H, dd, J 1.0, 8.0 Hz), 8.06 (2H, m), 7.98 (1H, d, J 8.6 Hz), 7.83 (1H, m), 7.77 (2H, m), 7.66 (1H, t, J 7.5 Hz), 7.54 (1H, dt, J 1.6, 7.7 Hz), 7.49 (1H, t, J 7.7 Hz), 7.42-7.38 (1H, m), 7.28 (1H, m), 7.21 (1H, m), 5.68-5.62 (1H, m), 2.51 (1H, d, J 3.2 Hz), 1.36 (3H, d, J 6.3 Hz); m/z (ES+) 389 [(M-OH)+].
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[CH2:18]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]([Cl:17])=[CH:15]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 1-benzyl-3-chloro-7-cyano-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 385 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([S:12]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CCCCCCC>[CH3:18][C:16]([CH3:17])([CH3:19])[CH2:15][S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:35]([C:34]3[CH:36]=[CH:37][C:31]([O:30][C:29]([F:38])([F:39])[F:28])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)(C)C)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Yield: 54.1 %

Procedure:
This material was prepared in analogy to example 1 step D) 1-(2,2-dimethyl-propane-1-sulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.17 g), dimethylaluminium chloride in heptane (1.0 molar, 1.46 ml) and 4-(trifluoromethoxy)-aniline (0.129 g) to give the desired 8-(2,2-dimethyl-propane-1-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.118 g) as an off-white solid. MS (ESI): 449.17 (MH+).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].CC([O-])=O.[Na+].[N+:13](CCO)([O-:15])=[O:14].C(Cl)(Cl)Cl>N1C=CC=CC=1.O>[C:1]([O:4][CH2:5][CH2:6][N+:13]([O-:15])=[O:14])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])CCO
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
This compound was prepared according to M. E. Flaugh, T. A. Crowell, J. A. Clemens, B. D. Sawyer J. Med. Chem., 1979, 22, pp. 63-68. Acetic anhydride (8.06 g, 79.0 mmol) and NaOAc (1.45 g, 17.7 mmol) were mixed and heated. Two drops of pyridine were added. 2-nitroethanol (6.45 g, 70.8 mmol) was carefully added to the suspension at 30-35° C. during 30 min. Thereafter the mixture was stirred overnight at room temperature. The next morning the mixture contained undissolved NaOAc and a new orange precipitate. The reaction mixture was taken up between CHCl3 and water, washed 1× with water, 1× with brine and dried with MgSO4. Thereafter the solvent was evaporated under reduced pressure at 40° C. The remaining orange oil was co-evaporated first with chloroform and then five times with toluene and finally with chloroform to get the 6.90 g of pure compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].[O:10]1[C:14]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:13][N:12]=[CH:11]1.O>CS(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]3[CH:17]=[CH:16][C:15]([C:14]4[O:10][CH:11]=[N:12][CH:13]=4)=[CH:22][CH:21]=3)[S:9][C:3]=2[CH:4]=1
Reactant: O=Cc1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Br)cc1S
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc2nc(-c3ccc(-c4cnco4)cc3)sc2c1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
2 Amino-5-bromobenzenethiol (102 mg) and 4-(1,3-oxazol-5-yl)benzaldehyde (87 mg) were dissolved in dimethylsulfoxide (1 mL), followed by stirring at 160° C. for 10 minutes. Water (10 mL) was added to the reaction mixture. The precipitated matter was recovered through filtration, and washed with methanol, to thereby yield the title compound (105 mg).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].CC([O-])(C)C.[K+]>CC(O)(C)C>[CH2:10]([N:9]([CH2:8][CH:7]1[CH2:6][NH:5][C:3](=[O:4])[CH2:2][O:24]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCl)NCC(O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1COC(CN(Cc2ccccc2)Cc2ccccc2)CN1

Procedure:
A solution of 2-chloro-N-(3-(dibenzylamino)-2-hydroxypropyl)acetamide (1.0 g, 2.49 mmol), t-BuOK (0.39 g, 3.57 mmol) in t-BuOH (30 mL) was stirred at reflux overnight. After concentration, the residue was purified by column chromatography to give product as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: OC1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: OC1CCN(c2ccc(C(F)(F)F)cc2F)C1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (137 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 ml) was stirred under an argon gas atmosphere at 85° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (2.82 g, yield 66%) as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1>CCOCC.C([O-])(=O)C.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][C:6]=1[Cl:11]
Reactant: O=[N+]([O-])c1c(Cl)nc(-c2ccccc2)nc1Cl
Agent: [Ni]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: Nc1c(Cl)nc(-c2ccccc2)nc1Cl
Yield: 72.5 %

Procedure:
27.0 g of 4,6-dichloro-5-nitro-2-phenylpyrimidine are hydrogenated in ether acetate at room temperature by treatment with Raney nickel. The catalyst is afterwards separated and the reaction solution is concentrated by evaporation. Crystallisation of the residue from petroleum ether then yields 17.4 g of 5-amino-4,6-dichloro-2-phenylpyrimidine, m.p. 143°-144° C. (compound No. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C(S([O-])(=O)=O)=CC=CN=3)[CH2:12]2)=[O:10])=[C:4]([C:33](=[O:40])[NH:34][CH:35]([CH:37]2[CH2:39][CH2:38]2)[CH3:36])[CH:3]=1.C(O)(=O)C.[BrH:45].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:45])[CH2:12]2)=[O:10])=[C:4]([C:33](=[O:40])[NH:34][CH:35]([CH:37]2[CH2:39][CH2:38]2)[CH3:36])[CH:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2ncccc2S(=O)(=O)[O-])=NN1c1ncccc1Cl)C1CC1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 1 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl3-pyridine sulfonate was dissolved in 0.7 mL of acetic acid, and 0.4 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about 1 hour. After completion of the reaction, ethyl acetate, water and 2.8 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 330 mg of the desired product in a paste form.
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][F:13])=[CH:6][CH:5]=1)=O.ClC1C=CC=C(C(OO)=O)C=1.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[SH:2][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][F:13])=[CH:8][CH:9]=1
Reactant: CS(=O)c1ccc(OCCF)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: FCCOc1ccc(S)cc1
Yield: 9.5 %

Procedure:
In a manner similar to Sugihara et al. (Synthesis, p 881 (1978)), the reaction of 8.7 grams (0.043 mole) of 2-fluoroethyl 4-methylsulfinylphenyl ether (Compound 80, prepared by the method of Example 4 using one equivalent of 3-chloroperbenzoic acid), 10.0 ml (0.086 mole) of 2,6-lutidine and 12.2 ml (0.086 mole) of trifluoroacetic anhydride in 160 ml of dry acetonitrile yielded 0.7 gram of 2-fluoroethyl 4-mercaptophenyl ether as an oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[F:23].O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])=[CH:18][C:17]=1[F:23]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc(Br)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(Br)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Diisopropyl azodicarboxylate (1.9 M solution in toluene, 83 mL) was added to a mixture of 4-bromo-3-fluorophenol (25.0 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (25.2 g), triphenylphosphine (41.2 g), and THF (250 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 30 min, and then at room temperature for 3 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.7 g) as a pale yellow solid.