Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25]>ClCCl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[F:25])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(O)cc1F
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1F)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-fluorophenol (Apollo), the title compound was obtained as a white solid after trituration in dichloromethane.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1)=O.O.[OH-].[Na+]>O1CCCC1>[CH3:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:8][C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH2:1])[CH2:11][CH2:12]1
Reactant: CC1CCN(C(=O)[C@@H]2CCCC[C@@H]2N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCN(C[C@H]2CCCC[C@H]2N)CC1

Procedure:
1-[Cis-(2-aminocyclohexyl)carbonyl]-4-methylpiperidine (6.57 g; 0.0293 mol) is dissolved in tetrahydrofuran (25 ml) and added dropwise to a suspension of AlLiH4 (2.22 g; 0.0586 mol) in tetrahydrofuran (50 ml). At the end of the addition, the reaction mixture is refluxed for 24 h and then hydrolyzed by carefully adding water (2.3 ml), then a 15% sodium hydroxide solution (2.3 ml) and then water (5 ml).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: COc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CN3C(=O)c4ccccc4C3=O)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.739 g 2-[3-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-isoindole-1,3-dione (prepared in Example 67) (4.79 mmol) was suspended in 50 cm3 abs. DMF and the flask was filled with argon properly. 347 mg Tetrakis(thriphenylphosphine) palladium[0] (0.3 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 968 mg 2-methoxyphenyl-boronic acid (6.50 mmol) and 2.123 g K3PO4 (3 mmol) was added. The mixture was ferluxed for 6 hours while slow argon flow was being applied. The reaction mixture was evaporated under reduced pressure, 150 cm3 5% NaHCO3 solution was added and it was extracted three times with 100-100 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated under reduced pressure. The residual oil was chromatographed on silica gel eluting with chloroform containing 1% ethyl-alcohol. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product as a yellow solid. Yield: 1.652 g (79%). For analitical results and compound identification see Table 1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[NH:7][CH2:6]1)[CH3:3].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:61]>C1COCC1>[ClH:61].[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:18][C:19]([CH2:22][O:15][C:10]2[CH:9]=[C:8]3[C:13]([CH2:14][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][NH:7]3)=[CH:12][CH:11]=2)=[CH:20][CH:21]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: CN(C)CC1CNc2cc(O)ccc2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(dimethylamino)methyl-1,2,3,4-tetrahydro-7-quinolinol (344 mg), 4-biphenylylmethanol (368 mg), and triphenylphosphine (525 mg) in THF (20 ml) was added diethyl azodicarboxylate (348 mg). After stirring at room temperature for one hr, the reaction mixture was poured into 1 N aqueous hydrochloric acid and washed with ethyl acetate. The water layer was neutralized by 1 N aqueous sodium hydroxide, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:4) and converted into its hydrochloride, which was further recrystallized from ethanol-diisopropyl ether to obtain the titled compound (214 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10](NC3C=NC4C(C=3)=CC=CC=4)[CH:9]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([OH:43])[CH:38]=1>CS(C)=O>[O:17]1[CH2:18][CH2:19][N:14]([C:12]2[N:13]=[C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)[CH:9]=[C:10]([O:43][C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[N:11]=2)[CH2:15][CH2:16]1
Reactant: Oc1cccnc1
Reactant: Nc1ncc(-c2cc(Nc3cnc4ccccc4c3)nc(N3CCOCC3)n2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncc(-c2cc(Oc3cccnc3)nc(N3CCOCC3)n2)cn1
Temperature: 110 °C
Yield: 42.7 %

Procedure:
5-(6-chloro-2-morpholinopyrimidin-4-yl)pyrimidin-2-amine (10 mg, 0.034 mmol, prepared as in example 1), potassium tert-butoxide (6 mg, 0.051 mmol), pyridin-3-ol (5 mg, 0.051 mmol) and DMSO (0.5 mL) were all combined together and heated at 110° C. for 2 days. The crude product was purified directly by preparative reverse phase HPLC to give 5-(2-morpholino-6-(pyridin-3-yloxy)pyrimidin-4-yl)pyrimidin-2-amine (5.1 mg, 32%). LC/MS (m/z): 352.1 (MH+), Rt 1.83 minutes.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](SC1C=CC=CC=1)=[CH:6][C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[Na].[ClH:61]>CO>[ClH:61].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:29][N:30]=[N:31][N:32]=2)=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCc1cc2c(c(CC)n1)CCC(=O)N2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C

Procedure:
5,7-Diethyl-1-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one (A) (5.0 g) was added to a solution of sodium (2.05 g) in methanol (100 ml) and the solution was heated at reflux for 16 hours under an atmosphere of argon. The mixture was cooled to 0° C. and acidified with concentrated hydrochloric acid (20 ml). The precipitated solid was collected by filtration and recrystallised successively from isopropanol (60 ml), water (30 ml) and ethanol (10 ml) to give 5,7-diethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one hydrochloride (2.36 g), m.p. 260-263° C. (decomposition); microanalysis, found: C, 65.6; H, 5.9; N, 17.8%; C26H26N6O.HCl requires: C, 65.7; H, 5.7; N, 17.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1(Br)[CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[C:7]([C:12]#[N:13])=[CH:8]2)[CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc2c(C#N)c[nH]c2c1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)cn(C3CCC3)c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To 6-methoxy-1H-indole-3-carbonitrile (98.2 g, 0.57 mol) was added cesium carbonate (430 g, 1.32 mol), DMF (165 mL) and cyclobutylbromide (96%, 67.5 mL, 0.69 mol). The mixture was heated to 90° C. and stirred overnight. The mixture was cooled to 37° C. and poured into ice water (500 mL), washing in with water. After stirring for 1 hour the precipitate was collected on a filter and dried under a stream of nitrogen to give 1-cyclobutyl-6-methoxy-1H-indole-3-carbonitrile as a tan solid (124.1 g, 96%).
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([NH:18][S:19]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])([CH3:17])[CH3:16].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:15]([NH:18][S:19]([C:22]1[NH:23][C:24]2[C:29]([C:30]=1[CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
To a solution of benzhydrol (0.58 g, 3.15 mmol) and N-isopropylindole-2-sulfonamide (0.7 g, 3.12 mmol) in 15 ml of methylene chloride was added a solution of methanesulfonic acid (0.2 ml, 3.12 mmol) in 4 ml of methylene chloride, followed by stirring at room temperature for 2.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization and the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.4 g of a crude product. The obtained crude product was washed with ethanol to give 1.07 g (yield: 85%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[F:16][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:17](=[O:19])[CH3:18])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[I:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of amine 107 (16.0 g, 47.6 mmol) in CH2Cl2 (150 mL) was treated with TEA (9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and the resulting reaction mixture was cooled to 0-5° C. before being treated with acetic anhydride (Ac2O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5 equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 equiv) at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 108 (17.36 g, 96.5% yield) as a white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH3). C12H12FIN2O3, LCMS (EI) m/e 379 (M++H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: Clc1ncc(Br)cn1
Product: Brc1cnc(N2CCCCC2)nc1

Procedure:
Prepared from 2-chloro-5-bromopyrimidine and piperidine by the method of Example 44 (b).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=[N:4][N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(O)C.C(=O)(O)[O-].[Na+]>[C:11]1([C:8]2[C:7]3[C:2]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:3][N:4]=[CH:5][C:6]=3[O:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1nncc2onc(-c3ccccc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CNc2nncc3onc(-c4ccccc4)c23)CC1
Temperature: 80 °C
Yield: 88.5 %

Procedure:
The compound prepared in Example 82 (202 mg), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.266 g) and triethylamine (0.607 mL) were combined in ethanol (1.5 mL) and heated at 80° C. for 17 hours. The reaction mixture cooled to room temperature, diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1 to 2:1) to obtain the title compound (316 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[C:9]2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[C:9]2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(CO)cn2-c2ccc(F)cc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(C=O)cn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
0.58 g (1.7 mmol) of 1-(4-fluorophenyl)-4-hydroxymethyl-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 46) was dissolved in 30 ml of methylene chloride, and 2.40 g of manganese dioxide were added to the resulting solution. The mixture was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of ethyl acetate and hexane, to give 0.52 g (yield 90%) of the title compound as a white powder, melting at 169-171° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2C(C)=CC3C(C)(C)CCC(C)(C)C=3C=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:3]([CH:16]([OH:17])[CH3:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C(=O)c1cc3c(cc1C)C(C)(C)CCC3(C)C)C(C)(C)CCC2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 4.17 g (17.1 mmol) of methyl[3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydronaphthalen-2-yl] ketone in methanol at 0° C. was portionwise added 0.77 g (20.4 mmol) of sodium borohydride and the resulting suspension stirred at 0° C. for 4 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 1N HCl, and extracted three times with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo and resulting residue purified using flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give a single isomer: the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][NH2:17]>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([NH:17][CH2:16][CH2:15][NH:14][CH3:13])=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: COc1ccc2c(Cl)noc2c1
Reactant: CNCCN
Product: CNCCNc1noc2cc(OC)ccc12
Temperature: 140 °C

Procedure:
To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (2.0 g) and N-methylethylenediamine (4.8 g). The reaction was heated to 140° C. over 48 hours and then cooled to room temperature. The residue was partitioned between EtOAc and brine, washed with brine (4×) and the organic phase was dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 5% acetone/CH2Cl2 provided a residue upon evaporation (0.4 g) m.p. 136°-137° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31](Cl)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:5]4)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 240 mg, 6.00 mmol, 3.00 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (642 mg, 2.80 mmol, 1.40 equiv) in freshly distilled tetrahydrofuran (14 mL) at 0° C. under nitrogen for 30 min. To this mixture was added a solution of (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (710 mg, 2.00 mmol, 1.00 equiv) in 5 mL of THF via syringe and the resulting solution was stirred overnight at room temperature. After completion, the reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (8:1) to give the desired tert-butyl N-(4-[[(3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (963 mg, 88%) as light yellow oil. MS: m/z 548 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]([OH:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:18]2[CH:19]=[CH:20][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: OC(c1ccc(Br)s1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CSc1ccc(-c2ccc(C(=O)C(F)(F)F)s2)cc1

Procedure:
1-(5-Bromo-4-thienyl)-1,2,2-trifluoroethanol (C1) in DUE added to Polymer-Bound Triphenylphosphine Pd(0) (0.5% eq) followed by 4-(methylthio)phenylboronic acid (1.3 eq)) in EtOH and K2CO3 (1.5 eq) in water and the mixture was stirred at 75° C. for 24 h. The suspension was filtered and the filtrate was purified by reverse phase HPLC as described for Example 3. MS (ES) C13H9F3OS2 requires: 302, found: 303 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:21]([O:30][CH2:31][C:32]#[C:33][CH2:34][OH:35])[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Br:36][C:37]1[CH:38]=[N:39][C:40](Cl)=[N:41][CH:42]=1>C1COCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[C:21]([O:30][C:31]#[C:32][CH2:33][CH2:34][O:35][C:40]3[N:41]=[CH:42][C:37]([Br:36])=[CH:38][N:39]=3)[N:20]=[CH:19][N:18]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)([CH3:5])([CH3:4])[CH3:6]
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCC#CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OC#CCCOc2ncc(Br)cn2)cc1
Reaction time: 1 h

Procedure:
To a suspension of 88 mg of a 55% sodium hydride dispersion in mineral oil in 15 ml of dry THF 375 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide (Example 12) was added. After stirring for 1 h, 170 mg of 5-bromo-2-chloropyrimidine was added. Stirring was continued for 60 h at 40° C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was crystallised from 2-propanol containing a small amount of diethyl ether to give 168 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as beige crystals. LC-MS: tR=6.22 min, [M+1]+=624.28.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[OH-].[K+].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.N#N>CN(C=O)C.CCOCC>[C:1]([C:4]1[N:5]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2]
Reactant: Fc1ccc(I)cc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccccc2n1-c1ccc(F)cc1
Reaction time: 6 h
Yield: 51.8 %

Procedure:
To a solution of 2-carboxy-1H-indole (50 g) in DMF (600 ml) were added potassium hydroxide (40 g) and 4-fluoroiodobenzene (90 g). Reflux in an inert N2 stream for 6 hours. H2O/DMF was distilled off to obtain a constant boiling point of 148° C. After cooling to room temperature ether (500 ml) was added. The precipitated material was filtered off and water (500 ml) was added. Undissolved material was filtered off. To the alkaline water phase was added ethyl acetate (500 ml) and pH was adjusted to 2 by addition of dil. aqueous HCl. The organic phase was worked up as yielding 2-carboxy-1-(4-fluorophenyl)-1H-indole (41 g) which melted at 213° C. The thus obtained carboxyindole (38 g) was added cautiously to a suspension of LiAlH4 (7.5 g) in dry THF (350 ml) at such a rate that the temperature was kept below 50° C. The mixture was finally stirred at 50° C. for 1.5 h. After cooling 5M NaOH solution was added under vigorous stirring. Precipitated inorganic material was filtered off and washed thoroughly with dichloromethane. After evaporation of the combined organic phases 1-(4-fluorophenyl)-2-hydroxymethyl-1H-indole (35 g) was isolated as a crystalline product. Mp: 65°-66° C. The hydroxymethyl derivative (35 g) was dissolved in ethanol (600 ml). The solution was hydrogenated in a Parr apparatus with 15% Pd/C as catalyst at 3 ato. for 20 h. The catalyst was filtered off and ethanol evaporated leaving the crude title compound 23a as an oil. Purification by elution (dichloromehtane/heptane 1:1 as eluent) through silica gel afforded the pure 1-(4-fluorophenyl)-2-methyl-1H-indole (18 g) as a crystalline product. Mp: 43° C.