Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)CC1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Methyl piperazine (0.072 mmol). The mixture can be microwaved at 120 degrees. The reaction mixture can then be filtered through a syringe filter and can be purified by prep-HPLC.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[CH:11][N:10]([C:13]3[S:14][C:15]([C:25]([NH2:27])=[O:26])=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)[N:17]=3)[C:9]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][NH:36][CH3:37]>[I-].[K+].CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([N:10]3[C:9]4[CH:28]=[C:5]([O:4][CH2:3][CH2:2][N:36]([CH3:37])[CH3:35])[CH:6]=[CH:7][C:8]=4[N:12]=[CH:11]3)[S:14][C:15]=2[C:25]([NH2:27])=[O:26])[CH:23]=[CH:22][CH:21]=1
Reactant: CNC
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCl)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2c1
Reaction time: 6 h
Yield: 76.9 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(2-chloro-ethoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.28a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.150 mL (0.3 mmole) of dimethylamine was stirred at 100 degrees for 6 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.034 g of 4-(3-chloro-phenyl)-2-[6-(2-dimethylamino-ethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.29) as a white powder. MH+/Z=442
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:35]=[CH:34][C:14]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:18]=3)=[O:16])=[CH:13][C:12]=2O)=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-:38].[K+].[K+].[Cl:43][CH:44](Br)[CH2:45][CH3:46].O>CN(C)C=O.C(OCC)(=O)C>[Cl:43][CH2:44][CH2:45][CH2:46][O:38][C:13]1[CH:12]=[C:11]([NH:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:35]=[CH:34][C:14]=1[C:15]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:18]=1)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)c(O)c2)c2ccccc21
Reactant: CCC(Cl)Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)cc2OCCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 4-{3-[4-(4-ethylphenyl)methylamino-3-hydroxybenzoyl]indol-1-yl}butanoate (39.3 g) was dissolved in N,N-dimethylformamide (200 ml), and potassium carbonate (22.4 g) and chlorobromopropane (24 ml) were added to the solution. The mixture was stirred at room temperature for four hours. The reaction mixture was poured into water, and ethyl acetate was further added for extraction. The formed organic layer was sequentially washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine, and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby obtain 44.8 g of ethyl 4-{3-[3-chloropropoxy-4-(4-ethylphenyl)methylaminobenzoyl]indol-1-yl}butanoate as a yellow oil. MS(m/z): 562(MH+); IR(CHCl3)cm−1:3450, 1730, 1595; NMR(CDCl3)δ:1.21(t, 3H), 1.25(t, 3H), 2.13˜2.36(m, 6H), 2.66(q, 2H), 3.72(t, 2H), 4.10(q, 2H), 4.21˜4.31(m, 4H), 4.43(d, 2H), 5.03(t, 1H), 6.59(d, 1H), 7.08˜7.50(m, 9H), 7.60(s, 1H), 8.31˜8.37(m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:38])[CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13](=[O:21])[C:12]=2[C:22]2[NH:26][C:25]3[CH:27]=[C:28]([N:32]4[CH2:37][CH2:36]N[CH2:34][CH2:33]4)[CH:29]=[C:30]([CH3:31])[C:24]=3[N:23]=2)[CH:5]=[CH:6][CH:7]=1.[C:39]([BH3-])#[N:40].[Na+].[CH3:43][OH:44]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:38])[CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13](=[O:21])[C:12]=2[C:22]2[NH:26][C:25]3[CH:27]=[C:28]([N:32]4[CH2:37][CH2:36][N:40]([CH2:39][CH2:43][OH:44])[CH2:34][CH2:33]4)[CH:29]=[C:30]([CH3:31])[C:24]=3[N:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: [BH3-]C#N
Reactant: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)c4ccccc4[nH]c3=O)nc12
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N2CCN(CCO)CC2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)c4ccccc4[nH]c3=O)nc12
Reaction time: 0.5 h

Procedure:
To a stirred solutionof 12 mg (0.023 mmol) of the 4-[(S)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazole-2-yl)-1H-quinoline-2-one in 0.5 mL of methanol was added ˜5 mg of glycaldehyde to which was added 0.3 mL of 1 N solution of sodiumcyanoborohydride in tetrahydrofuran, and the mixture was stirred for 30 minutes, and then it was subjected to preparative HPLC to afford the product. LRMS [M+H]+573; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=7.96 Hz), 7.97 (s, 1H), 7.64 (dd, 1H, J=7.97, 8.4 Hz), 7.03-7.36 (m, 7H), 4.77 (m, 1H), 3.94 (t, 1H, J=5.1 Hz), 3.42-3.52(m, 8H), 3.36 (t, 1H, J=5.1 Hz), 3.31-3.47 (m, 4H), 2.63 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8]Cl)(=O)=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:4]1[CH2:7][CH2:8][C:11]([C:10]#[N:14])([C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: O=S(=O)(CCCl)CCCl
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC1(C#N)CCSCC1
Yield: 34.9 %

Procedure:
A mixture of 38.2 g of bis(2-chloroethyl)sulfone, 13.2 g of malononitrile, 55.28g of potassium carbonate and 800 ml of acetonitrile is refluxed on a steam bath for 24 hours, then filtered while hot. The filtrate is evaporated and the residue crystallized with charcoal treatment from 100 ml of ethanol, giving 10.6 g of tetrahydro-4H-thiopyran-4,4-dicarbonitrile, 1,1-dioxide as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:15]=[C:14]([N:16]3[C:24]4[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=4[N:18]=[CH:17]3)[S:13][C:12]=2[C:27]([NH2:29])=[O:28])[CH3:9])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl>[CH3:34][S:35]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[C:30]([F:33])([F:31])[F:32])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:37])=[O:36]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 120 mg of 3-{1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 57 mg of methanesulfonyl chloride, and 51 mg of triethylamine in 3 ml dichloromethane give [1-(5-carbamoyl-4-{1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [O-:1][S:2](S([O-])=O)=[O:3].[Na+].[Na+].O.[CH:10]([C:13]([C:16]([C:19]([C:22]([C:25]([CH2:28]I)([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11]>C(#N)C>[CH:10]([C:13]([C:16]([C:19]([C:22]([C:25]([CH2:28][S:2]([OH:1])=[O:3])([F:26])[F:27])([F:23])[F:24])([F:20])[F:21])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11]
Reactant: O=S([O-])S(=O)[O-]
Reactant: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CI
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S(O)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 70 °C
Yield: 94 %

Procedure:
Na2S2O4 (260 mg, 3.0 mmol) was poured into a 20 ml flask and the inside of the flask was replaced with argon. Water (5.0 ml) was added thereto and then, H(CF2)6CH2I (442 mg, 1.0 mmol) was added dropwise using acetonitrile (5.0 ml). After ten-hour stirring at 70° C., purification was conducted by adding 3N—HCl to the reaction product, extracting with ether, extracting into water layer with an aqueous solution of saturated NaHCO3, again making the solution acidic with hydrochloric acid and then extracting into ether layer. After distilling off the solvent, drying was carried out under reduced pressure to obtain H(CF2)6CH2SO2H (359 mg, 0.94 mmol).
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[CH2:3][C:2]1=[O:7].[F:8][C:9]([F:15])([F:14])[CH2:10][C:11](O)=[O:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CC#N>[OH:6][C:4]1[CH2:5][O:1][C:2](=[O:7])[C:3]=1[C:11](=[O:12])[CH2:10][C:9]([F:15])([F:14])[F:8]
Reactant: O=C(O)CC(F)(F)F
Reactant: O=C1COC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(CC(F)(F)F)C1=C(O)COC1=O
Temperature: 0 °C

Procedure:
To a cool (0° C.), stirred suspension of furan-2,4(3H,5H)-dione (16.46 g, 164 mmol) in DCM (650 mL) was added TEA (23.0 mL, 165 mmol), DMAP (6.04 g, 49.4 mmol), 3,3,3-trifluoropropanoic acid (16.0 mL, 181 mmol) and DCC (40.70 g, 197 mmol) resulting in a yellow homogenous solution. The solution was stirred at 0° C., and then was allowed to warm to room temperature as the bath warmed while stirring overnight. The suspension was filtered and the solid was washed with DCM. The deep red filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and 1M HCl (400 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford an amber solid. This was dissolved in a minimum amount of CH3CN, to which DCM was added to form a precipitate. The suspension was allowed to stand in the freezer overnight. It was sonicated then cooled and filtered, the solid was washed with cold DCM and then dried to provide Preparation 1A (31.62 g, 91%) as a cream solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (1H, br. s.), 4.29 (2H, s), 3.80 (2H, q, J=11.67 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH:8]1[O:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]2.C(Cl)Cl>CCOCC.Cl([O-])(=O)(=O)=O.[Li+]>[O:9]1[C@@H:10]2[C@H:4]3[C@H:3]([C@H:8]1[C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=12)[C@H:2]([CH3:1])[O:6][C:5]3=[O:7]
Reactant: c1occ2c1CCCC2
Reactant: C[C@H]1C=CC(=O)O1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]2[C@@H]1[C@@H]1O[C@H]2C2=C1CCCC2
Temperature: 25 °C
Reaction time: 168 h
Yield: 58.2 %

Procedure:
To 224.0 mg(2.28 mmol) of (S)-5-methyl-2(5H)-furanone were added 557.9 mg(1.5 equivalents) of 4,5,6,7-tetrahydroisobenzofuran in 2 ml of dehydrated ether solution and 1.06 g of lithium perchlorate, and, after flushing with argon, the mixture was stirred for 168 hours at room temperature. The reaction mixture was poured into 20 ml of water, which was extracted with methylene chloride(10 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography(methylene chloride, then methylene chloride:ethyl acetete=10:1) to obtain 292.2 mg of (3S, 3aS, 4S, 9R, 9aR)-4,9-epoxy-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one (yield 58%).
Reaction SMILES: [C:1]([Si:3]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5])#[CH:2].Br[C:14]1[CH:15]=[CH:16][C:17]([F:21])=[C:18]([OH:20])[CH:19]=1.C(N(CC)CC)C>CN(C=O)C.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[F:21][C:17]1[CH:16]=[CH:15][C:14]([C:2]#[C:1][Si:3]([CH:7]([CH3:9])[CH3:8])([CH:4]([CH3:6])[CH3:5])[CH:10]([CH3:12])[CH3:11])=[CH:19][C:18]=1[OH:20]
Reactant: Oc1cc(Br)ccc1F
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[Si](C#Cc1ccc(F)c(O)c1)(C(C)C)C(C)C

Procedure:
A solution of Ethynyl-triisopropyl-silane (1.13 g, 6.20 mmol), 5-bromo-2-fluorophenol (0.955 g, 4.98 mmol), bis(triphenylphosphino)palladium(II) chloride (0.105 g, 0.15 mmol), copper iodide (0.039 g, 0.205 mmol) and triethylamine (2.9 g, 28.7 mmol) in DMF (4.0 mL) is irradiated in the CEM explorer at 80° C. for 30 min. The solvent is removed and the product purified by Flash Chromatography to yield 2-fluoro-5-((triisopropylsilyl)ethynyl)phenol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].Cl.Cl.[NH2:18][C@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@H:19]([NH:18][C:12]([C:10]1[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=3[CH:9]=1)=[O:14])[CH2:20]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
187 mg (0.90 mmol) of 5-nitrobenzofuran-2-carboxylic acid, 150 mg (0.75 mmol) of (S)-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90 mmol) of HATU, 350.5 mg (3.71 mmol) of N,N-diisopropylethylamine and 5 ml of DMF are reacted according to the general procedure (variant B). 169.1 mg (70% of theory) of the title compound are obtained. The analytical data correspond to those of the enantiomeric compound from example 30.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:13][CH3:14])[C:3]([OH:12])([C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)[C:4]#[CH:5].I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(#N)C>[OH:12][C:3]([C:6]1[CH:11]=[N:10][CH:9]=[N:8][CH:7]=1)([C:2]([CH3:15])([CH3:1])[CH2:13][CH3:14])[C:4]#[C:5][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Ic1cccnc1
Reactant: C#CC(O)(c1cncnc1)C(C)(C)CC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)(C)C(O)(C#Cc1cccnc1)c1cncnc1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 128 %

Procedure:
A stirred mixture of 4,4-dimethyl-3-hydroxy-3-pyrimidin-5-ylhex-1-yne (412 mg, 2 mmol), 3-iodopyridine (412 mg, 2 mmol), triethylamine (300 μl, 2.2 mmol), copper-I-iodide (20 mg), and bis(triphenylphosphine) palladium-II-chloride (20 mg) in dry acetonitrile (5 ml) under nitrogen was heated at 65° C. After 40 minutes, the reaction was cooled and quenched with dilute aqueous hydrochloric acid. The mixture was neutralised with ammonia, extracted with ethyl acetate (3×20 ml), and the organic extracts were combined. Washing with ammonia, water, and brine, drying over magnesium sulphate and concentration under reduced pressure gave yellow crystals (720 mg). Recrystallisation from ethyl acetate gave the desired product of melting point 170.5°-171.5° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[F:33][C:21]([F:20])([F:32])[C:22]1[CH:23]=[C:24]([S:28]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:29])=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Product: O=S(=O)(Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.081 g) as a light yellow gum (0.114 g). MS (ESI−): 475.0 ([M−H]−).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1.[H][H].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>CN(C=O)C>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:9]=1
Reactant: Fc1ccccc1CBr
Reactant: [H][H]
Reactant: CCOC(=O)CCSCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSCc1ccc(OCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of NaH (60% dispersed in oil, 0.054 g, 1.3 mmol) in dry DMF (10 ml) was added Ethyl 3-((4-hydroxyphenyl)-methylthio)propionate (Step B, 2.5 g, 1.0 mmol). When the evolution of hydrogen ceased, 2-Fluorobenzyl bromide (0.263 g, 1.3 mmol) was added. The reaction mixture was stirred for 4 hours at room temperature, quenched with sat. NH4Cl, and concentrated in vacuo. The crude residue was taken in EtOAc and washed twice with water and brine. The aqueous layer was washed one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (hex:ethyl acetate, 4:1) to provide the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]1[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=1[NH2:22])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=O>ClCCCl>[Si:1]([O:8][CH2:9][C@@H:10]([N:12]1[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=2[N:22]=[C:32]1[CH2:31][Cl:30])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)c(N)c(N[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1C
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c2nc(CCl)n([C@@H](C)CO[Si](C)(C)C(C)(C)C)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
N4-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5,6-dimethylpyridine-3,4-diamine (2.85 g, 8.29 mmol) was dissolved in 100 mL of dry 1,2-dichloroethane and the solution was cooled to 0° C. as it stirred under an atmosphere of N2. Triethylamine (2.3 mL, 16.58 mmol) and chloroacetyl chloride (0.92 mL, 11.60 mmol) were added sequentially. After 30 minutes, the reaction mixture was allowed to warm to ambient temperature and stirred for 3 days followed by heating to 70° C. for 2 days. The reaction mixture was allowed to cool to ambient temperature and was washed with saturated NaHCO3 solution (2×100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a brown solid. Chromatography (SiO2, 20-50% ethyl acetate/hexanes) gave 1-((1S)-2{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-4-chloro-2-(chloromethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridine (0.44 g) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[CH3:26])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (85 μL, 0.62 mmol) in methylene chloride (15 mL) was added dropwise 2-methylbenzoyl chloride (66 mg, 0.43 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3.5) as the eluent. Yield: 100 mg (80%) of the title compound as white crystals: mp 179-180° C.; [α]21D -22° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 363 (21, M+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].[OH-].[Na+].C(OCC)(=O)C>CN(C=O)C>[F:15][CH:11]([F:16])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.8 %

Procedure:
4-Cyanophenol (0.50 g, 4.2 mmol, Aldrich), sodium chlorodifluoroacetate (0.77 g, 5 mmol, Alfa Products), and sodium hydroxide (0.20 g, 5 mmol) were combined in dry DMF (2 mL) under an atmosphere of argon. After stirring at 125°-130° C. for 5 h, the mixture was cooled to RT, ethyl acetate (50 mL) was added and the organic layer was washed twice with brine. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes) to provide a white solid. The solid was sublimed (1 mm Hg, 23° C.) to provide the title compound as colorless crystals (0.29 g, 41%). mp 33°-35° C.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7])C>CO.[OH-].[Na+]>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([S:9][CH:5]([CH:6]([CH3:8])[CH3:7])[C:4]([OH:18])=[O:3])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Sc1ccc(OC)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(SC(C(=O)O)C(C)C)cc1

Procedure:
2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester (5.8 g, 21.6 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 1. Yield 5.0 g, 99%. Low melting sold. MS: 242 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[CH:7]1.C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[C:10]([CH:11]=[O:12])=[CH:9][N:8]=[CH:7]1
Reactant: OCc1cncn1Cc1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cncn1Cc1cccc(I)c1
Reaction time: 0.67 h

Procedure:
To a solution of the alcohol from Step B (ca. 10.4 mmol) in 100 mL of DMSO at room temperature was added triethylamine (14.5 mL, 104 mmol), then SO3-pyridine complex (8.27 g, 52 mmol). After 40 minutes, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as an oily solid contaminated with triethylamine.