Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[C:42]([O:48][CH3:49])[CH:41]=1>CC#N>[NH2:45][CH2:44][C:43]1[CH:46]=[CH:47][C:40]([CH2:39][N:18]([CH2:17][C:9]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:41][C:42]=1[O:48][CH3:49]
Reactant: COc1cc(CBr)ccc1C#N
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)ccc1CN
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.386 g, 1.02 mmol) in CH3CN (10 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.00 mmol) followed by of 4-(bromomethyl)-2-methoxybenzonitrile (0.363 g, 1.60 mmol). The resultant mixture was heated to 60° C. for 15 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (40 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) followed by radial chromatography on silica gel (2 mm plate, 2:1 hexanes-EtOAc) provided 0.30 g (56%) of a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1>>[CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: BrCc1ccc2ccccc2c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc3ccccc3c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-naphthalene following the procedure of Example 478: MS (ESI) m/z 534.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Br:30])[C:21]=1[CH2:22]Br>C1COCC1.C(Cl)(Cl)(Cl)Cl>[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Br:30])[C:21]=1[CH2:22][CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COc1cc(Br)c(CBr)c(Br)c1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Br)c(CCC(=O)OC(C)(C)C)c(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 5 mL of THF at −78° C. was added 6.5 mL of a 1.0M solution of lithium hexamethyldisilazane in THF. t-Butyl acetate (0.9 mL) was added dropwise to the resulting cold solution, and the resulting mixture was stirred for 10 min at −78° C. 2,6-Dibromo-4-methoxy-benzyl bromide (1.2 g) in 5 mL of CCl4 was added dropwise over 5 min. The mixture was stirred 20 min at −78° C., then quenched by addition of 1 mL of saturated aqueous NaHCO3. The mixture was warmed to room temperature, diluted with 50 mL of saturated aqueous NaHCO3, and extracted with 3×20 mL of EtOAc. The combined organics were washed with 25 mL of brine, dried over MgSO4, and concentrated to yield t-Butyl 3-(2,6-dibromo-4-methoxyphenyl)-propionate as an oily yellow solid. Mass spectrum (ESI) 320.9 (M-OtBu). 1H NMR (500 MHz, CDCl3): δ 7.08 (s, 2H); 3.76 (s, 3H); 3.20 (m, 2H); 2.45 (m, 2H); 1.47 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:28])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[C:9]([CH3:16])=[N:10]2.CO.[OH-].[Na+]>C(O)=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:16])[C:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=1)=[C:7]2[CH3:28]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Cc1nc2c(Cl)ccc(CC(=O)O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of [8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-yl]acetic acid methyl ester (0.050 g), methanol (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.63 mL) was stirred at room temperature for 18 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (30% to 70% of organic modifier) gave title compound as a white solid, 0.0060 g.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([Cl:15])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Cl:15][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=1)([C:3]#[N:4])[CH3:16])[CH:14]=2
Reactant: CC(N)(C#N)Cn1cc2ccc(Cl)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg, described in Example 132) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (37 mg, 98%). MS (ES): M/Z [M+H]=439. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s, 3H), 4.81 (d, 1H), 4.89 (d, 1H), 7.12 (dd, J=9.0, 1.6 Hz, 1H), 7.65 (d, J=9.0, 1H), 7.69 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 8.18 (s, 1H) and 8.58 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(#N)C>CCOCC>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])#[N:21]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
0.05 g of boron trifluoride ether complex was added to a mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.02 g of o-aminobenzonitrile and 5 ml of acetonitrile followed by agitation at room temperature for 5 minutes. Ether was added to the reaction mixture, and the resultant crystals were collected by filtration and dried to give 2.2 g of 1-(2-cyanophenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([CH2:19][NH:20][C:21](=[O:35])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:24][CH:23]=2)[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][C@H:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:15]([O:17][CH3:18])=[O:16])=[O:35])=[CH:23][CH:24]=1
Reactant: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
520 mg of 10 wt % palladium on carbon are added to a solution of 5.2 g (10.7 mmol) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methoxyethoxymethoxy)-benzoylamino]propanoate (prepared as described in example 22-4) in 80 ml of ethanol previously degassed under a stream of nitrogen, and the mixture is placed under hydrogen at atmospheric pressure. After stirring for 18 h at ambient temperature, the reaction medium is filtered over celite. The filtrate is concentrated to give 3.8 g (90%) of methyl (S)-3-[4-(2-methoxyethoxy-methoxy)benzoylamino]-2-piperazin-1-ylpropanoate in the form of a colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[S:18])[NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16]C)=O)[CH2:4][CH3:5].[CH3:19]I>O1CCCC1>[CH3:19][S:18][C:7]1[N:6]([CH2:3][CH2:4][CH3:5])[C:14](=[O:16])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[N:8]=1
Reactant: CI
Reactant: CCCNC(=S)Nc1sccc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(SC)nc2sccc2c1=O
Yield: 91.1 %

Procedure:
In a sulfonation flask, 2.9 g (0.072 mol) of a ca. 60% sodium hydride dispersion is added to 50 ml of absolute tetrahydrofurane. Then 17.7 g (0.069 mol) of methyl 2-(3-propylthioureido)thiophene-3-carboxylate, dissolved in 100 ml of absolute tetrahydrofurane, are added dropwise, such that the internal temperature remains constant at about 25° C. The mixture is stirred at reflux temperature for 5 hours and after cooling to room temperature 10.9 g (0.077 mol) of methyliodide, dissolvedin 10 ml of tetrahydrofurane, are added dropwise. Then the mixture is stirred another 2 hours at reflux temperature. After completion of the reaction, the tetrahydrofurane is removed in the waterjet vacuum and the residue taken up in ethyl acetate. The organic layer is washed twice with water and then dried over sodium sulfate. After removal of the solvent in the water-jet vacuum, the crude product is obtained, which is purified by digestion in n-hexane. 15.1 g of 2-methylsulfanyl-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are obtained in the form of a slightly yellowish powder having a melting point of 94-96° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:8]=2[CH:18]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C.[Fe]>[C:12]1([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][C:8]=3[CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccccc3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 80 °C
Yield: 97 %

Procedure:
To 5-Nitro-2-phenylbenzofuran (250 mg, 1.04 mmol) in ethanol/water 2:1 v/v (12 mL) at 80° C. was added ammonium chloride (112 mg, 2.09 mmol) and iron powder (292 mg, 5.23 mmol). The resulting mixture was heated at 80° C. for 4 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. The organic layer was evaporated into vacuo to obtain a solid, which was then taken up in ethyl acetate and washed with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 211 mg (96%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[CH:20]=2)[CH:14]=1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[CH:20]=2)[CH:14]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(-c3cc(C)no3)c2)c(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2cc(Oc3ccc(N)nc3C)ccn2)on1
Temperature: 60 °C
Yield: 94 %

Procedure:
A mixture of N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (0.11 g, 0.339 mmol) and 2M HCl (1.696 mL, 3.39 mmol) in THF (3 mL) was heated at 60° C. for 4 h. The mixture was cooled to RT, treated with EtOAc and H2O, neutralized with NaHCO3, the layers separated and the aqueous layer extracted with EtOAc (1×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (90 mg, 94%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=5.7 Hz, 1H); 7.26 (d, J=2.5 Hz, 1H); 7.22 (d, J=8.7 Hz, 1H); 6.95 (s, 1H); 6.89 (dd, J=5.7, 2.5 Hz, 1H); 6.36 (d, J=8.7 Hz, 1H); 6.00 (s, 2H); 2.28 (s, 3H); 2.06 (s, 3H); MS (ESI) m/z: 283.1 (M+H+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>CCCCC>[CH3:4][CH:2]1[O:3][CH:8]([CH:7]([CH3:17])[CH3:12])[O:5][C:1]1=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@H](O)C(=O)O
Solvent: CCCCC
Product: CC1OC(C(C)C)OC1=O
Yield: 869816.19 %

Procedure:
43.6 g (0.60 mol) of isobutyl aldehyde, 62.5 g (0.55 mol) of L-lactic acid, and 1.06 g (0.05 mmol) of p-toluene sulfonic acid were dissolved in 50 ml of n-pentane, and the mixture was refluxed for 8 hours in a 500-ml flask attached to a reflux condenser comprising a Dean-Stark fractionator. After the reaction, the reaction mixture was neutralized and washed with a sodium bicarbonate aqueous solution, followed by extraction with ether. Thereafter, the extract was dried with anhydrous magnesium sulfate. Thereafter, ether was distilled off, thereby giving 62.7 g (yield=79.2%) of 5-methyl-2-isopropyl-1,3-dioxolan-4-one as a diastereomer mixture.
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][C:8]1[C:9]([CH2:14][CH3:15])=[N:10][O:11][C:12]=1[CH3:13]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:14]([C:9]1[C:8]([NH2:7])=[C:12]([CH3:13])[O:11][N:10]=1)[CH3:15]
Reactant: CCc1noc(C)c1NC(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1noc(C)c1N
Yield: 41.7 %

Procedure:
A solution of (3-ethyl-5-methylisoxazol-4-yl)-carbamic acid 2-trimethylsilanylethyl ester (1.8 g) in tetrabutylammonium fluoride (26.7 ml of a 1.0M solution in tetrahydrofuran) was heated at 50° C. for 30 mins. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (150 ml), washed with sodium hydrogencarbonate solution (30 ml), washed with water (30 ml) and washed with brine (30 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50-100% ethyl acetate in hexane afforded the title compound as a yellow oil (0.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:26])[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Br)cc2C2CCCC12F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: FC12CCCC1c1cc(Br)ccc1NC2=S

Procedure:
A solution of 0.74 g (2.6 mmol) of 8-bromo-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 100 ml of THF is refluxed with 2.16 g (5.34 mmol) of Lawesson's reagent for 1.5 hours. Then, the reaction mixture is concentrated by evaporation, and the residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 0.59 g of product.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:47]>>[ClH:47].[ClH:47].[ClH:47].[SH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([SH:32])=[CH:30][CH:31]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCCN(Cc1ccc(S)cc1)C(=O)OC(C)(C)C)CCCN(Cc1ccc(S)cc1)C(=O)OC(C)(C)C
Agent: Cl
Product: Sc1ccc(CNCCCNCCCNCc2ccc(S)cc2)cc1

Procedure:
Dissolve 1,9-bis[(4-mercaptophenyl)methyl]-1,5,9-tri(t-butyloxycarbonyl)-1,5,9-triazanonane (4.75 g, 10 mmol) in saturated methanolic hydrochloric acid (100 mL). Stir for several hours and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1
Reactant: O=C1CN(c2ccc(/C=C/c3cccnc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CN(c2ccc(/C=C/c3cccnc3)cc2O)S(=O)(=O)N1
Reaction time: 0.5 h

Procedure:
To a solution of 5-[2-benzyloxy-4-((E)-2-pyridin-3-yl-vinyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (52 mg, 0.123 mmol) in methylene chloride (2 mL) at 0° C. is added BBr3 (0.247 mL, 1M in methylene chloride, 0.247 mmol) slowly and the mixture is stirred for 30 min. The mixture is quenched with 1N HCl and extracted with EtOAc. A yellow precipitate forms in the aqueous layer and is filtered and dried under reduced pressure to give the title compound: (M−1)−=330; HPLC retention time=0.77 min (method A).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3.3 g), piperidine, (2.5 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (2.6 g), melting at 160° C., is obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12](O)=O)[C:8]([F:15])=[C:7]([F:16])[C:3]=1[C:4](O)=O.B>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[C:9]([CH3:12])[C:8]([F:15])=[C:7]([F:16])[C:3]=1[CH3:4]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: B
Solvent: C1CCOC1
Product: Cc1c(F)c(F)c(C)c(F)c1F

Procedure:
To a stirred solution of perfluoroterephthalic acid (1.0 g, 4.2 mmol) in anhydrous THF (10 ml) under an atmosphere of dry argon was added Borane. THF complex (1.0M solution in THF, 10 equivalents, 42 ml) dropwise, and the mixture stirred at room temperature overnight. The solution was evaporated under reduced pressure to give a colourless oil and the excess Borane destroyed by addition of anhydrous methanol (40 ml) and evaporation (repeated three times). The residue was treated with 5% aqueous hydrocMoric acid then the pH of the mixture was adjusted to pH9 with 1N aqueous sodium hydroxide solution and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2,3,5,6-tetrafluoro-p-xylene-∝,∝′-diol (0.75 g, 86%) as a white solid. This was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>O.C(O)C.C(OCC)(=O)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH3:11][C:10]1[C:5]2[N:4]([C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:2]([CH3:1])[CH:6]=2)[CH2:7][CH2:8][N:9]=1
Reactant: CC(=O)NCCn1ccc(C)c1-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=NCCn2c1cc(C)c2-c1ccccc1
Yield: 30 %

Procedure:
N-[2-[3-Methyl-2-phenylpyrrol-1-yl]ethyl]acetamide (2.6 g) was treated with 20 ml of phosphorus oxychloride under argon and boiled under reflux for 1 hour. the reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 100 ml of 28% sodium hydroxide solution, diluted with 1000 ml of water and extracted with methylene chloride (1×300 ml, 2×150 ml). The organic extracts were combined, washed once with 100 ml of water, dried with MgSO4 and freed from solvent. 2.1 g of crude product were dissolved in a 25-fold amount of ethanol at the boiling temperature and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. After the addition of 50 ml of ethyl acetate 2.0 g of pale yellow crystals separated and were recrystallized from ethyl acetate/ethanol (1:1). There were obtained 1.3 g (30%) of 3,4-dihydro-1,7-dimethyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (2:3); m.pt.: 157°-159° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[CH2:32][OH:33]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH3:25])=[O:23])=[C:3]([CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH2:32][OH:33])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: OC[C@H]1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: COC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 44.2 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.44 g, 44%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.[CH3:10][Si:11]([CH3:29])([CH3:28])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=[C:17]1B(O)O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:29])([CH3:28])[CH3:10])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:5]([OH:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(B(O)O)cc2cccnc21
Reactant: Oc1ccc(Cl)nc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(-c2nc(Cl)ccc2O)cc2cccnc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a mixture of 6-chloro-2-iodopyridin-3-ol (8.39 g, 32.85 mmol), (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (8.00 g, 27.38 mmol) and K3PO4.3H2O (22 mg, 82.13 mmol) in 1,4-dioxane (120 mL), Pd(dppf)Cl2 (50 mg) was added under N2 protection. After stirred overnight at 80° C., the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=5:1) to provide the product of 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-3-ol (3.01 g, yield: 29%). 1H-NMR (CDCl3, 400 MHz) δ 8.40 (dd, J=4.8 Hz, 1.6 Hz, 1H), 7.96 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.82 (s, 1H), 5.85 (s, 2H), 3.65 (t, J=8.4 Hz, 2H), 0.89 (t, J=8.4 Hz, 2H), −0.08 (s, 9H). MS (M+H)+: 376/378.