Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[NH2:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[OH-].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH2:14])[CH:20]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 16.1 %

Procedure:
2-Fluoro-4-nitrophenol (1.736 g) was dissolved in dimethyl sulfoxide (10 ml), and sodium hydride (400 mg) was added thereto, followed by stirring for 20 min. Then, 4-Amino-6-chloropyrimidine (648 mg) was added thereto and stirred at 100° C. for 45 min. The reaction mixture was heated up to 120° C. and stirred for 1 hr 25 min. The reaction mixture was then heated up to 140° C. and stirred overnight. The reaction mixture was allowed to cool down to room temperature, a 1N aqueous solution of sodium hydroxide (10 ml) was added thereto and stirred, then extracted with ethyl acetate. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). The solvent was concentrated under reduced pressure, the resultant residue was suspended in diethyl ether (7 ml)-hexane (3.5 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as pale brown powder (201 mg, 16.0%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[Cl:16].C[O:18][B:19](OC)[O:20]C.Cl>C1COCC1>[Cl:16][C:8]1[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[CH:11]=[CH:12][C:7]=1[B:19]([OH:20])[OH:18]
Reactant: CCOc1ccc(Br)c(Cl)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 1-bromo-2-chloro-4-ethoxybenzene (19.5 mmol, 4.59 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming a white precipitate. The white precipitate (2.25 g, 58%) was filtered and dried to afford (2-Chloro-4-ethoxyphenyl)boronic acid. 1H NMR (CDCl3, 300 MHz): 7.87 (1H, d, J8.4 Hz), 6.88 (1H, d, J 2.5 Hz), 6.84 (1H, dd, J 8.4 and 2.5 Hz), 5.53 (2H, br. s), 4.06 (2H, q, J 7.07 Hz), 1.42 (3H, t, J 7.0 Hz.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Br:10]Br>C(O)(=O)C>[Br:10][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: BrBr
Reactant: CSc1nccc(C)n1
Solvent: CC(=O)O
Product: CSc1nccc(CBr)n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a solution of 4-methyl-2-methylthiopyrimidine (12.6 g, 0.09 mol) in acetic acid (50.0 mL) was added bromine (5.5 mL, 0.11 mol) and heated at 80° C. under argon atmosphere for 2 h. Acetic acid was distilled in vacuo, the residue was triturated with dichloromethane (100.0 mL) and poured into satd. sod.bicarbonate solution (200.0 mL). Additional dichloromethane (100.0 ml) was added and stirred for 15 min. The organic phase was washed with water (3×100 mL), dried (Na2SO4), and concentrated under reduced pressure. The dark colored residue was purified by flash chromatography (EtOAc/hexane 1:4 v/v) to afford 4-(bromomethyl)-2-(methylthio)pyrimidine (10.9 g, 55%) as a dark colored liquid: 1H NMR (CDCl3/400 MHz) δ 8.50 (d, 1H, J=4.8 Hz), 7.09 (d, 1H, J=4.8 Hz), 4.34 (s, 2H), and 2.56 (s, 3H); ES MS m/z 219 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:29][CH3:30])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:29][CH3:30])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([OH:3])=[O:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2Cc2ccccc2C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2Cc2ccccc2C(=O)O)c1
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of 75 mg (0.17 mmol) of the product of Example 14, Step B in 3 mL of methanol was added 2.0 mL of 1N NaOH. The mixture was stirred for 16 hours. The volatiles were removed in vacuo and the water removed azeotropically with toluene. The clear oil was flash chromatographed with 80:20:2 CHCl3 /methanol/NH4OH to yield the titled compound (58 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.[CH3:36][S:37]([O-:39])=[O:38].[Na+]>CN1C(=O)CCC1.[Cu](I)I>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:37]([CH3:36])(=[O:39])=[O:38])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1
Reactant: CS(=O)[O-]
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(S(C)(=O)=O)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
{3-[4-Bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester (0.1 g, 0.19 mmol), sodium methanesulfinate (0.087 g, 0.84 mmol), and copper iodide (0.159 g, 0.84 mmol) were combined in NMP (2 mL) and degassed with N2 for 10 minutes. The reaction was then stirred at 150° C. for 3 hours, until no starting material was seen by analytical tlc. The mixture was filtered through Celite and worked-up with brine and EtOAc, and the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15](OCCOCC)=[O:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CCOCCOC(=O)c1ccnc(Nc2ccc(Cl)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccnc(Nc2ccc(Cl)cc2)n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A suspension of 2-ethoxyethyl 2-((4-chlorophenyl)amino)pyrimidine-4-carboxylate (0.4 g, 1.243 mmol) in THF (12 mL) was cooled to −78° C. and a 1M solution of DIBAL-H (4.97 mL, 4.97 mmol) in toluene was added. The mixture was stirred for 1.5 h at room temperature. The reaction mixture was diluted with THF (20 mL) and quenched with Na2SO4.10H2O followed by a few drops of water. The mixture was stirred at room temperature for 18 h, then filtered through a pad of Celite topped with silica gel. The pad was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 75-100% ethyl acetate in hexanes. The desired fractions were concentrated to give (2-(4-chlorophenylamino)pyrimidin-4-yl)methanol as a pale yellow solid (0.224 g, 76%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.41 (1H, d, J=5.02 Hz), 7.55-7.86 (2H, m), 7.19-7.40 (2H, m), 6.95 (1H, d, J=5.02 Hz), 4.57 (2H, s). LCMS: R.T.=3.10; [M+H]+=236.12.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[ClH:14].[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=4)[NH:3][C:2]=3[CH3:1])=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccnc2cc(Cl)ccc12
Temperature: 160 °C
Yield: 95.6 %

Procedure:
A mixture of 2-methyl-5-nitroindole (1.34 g) and 4,7-dichloroquinoline (1.53 g) in NMP (1 ml) and 4M HCl in dioxane (0.1 ml) was heated at 145° C. for 2 hours and at 160° C. for 4 hours. After cooling the mixture triturated with ether and the solid collected to give the sub-title compound (2.72 g) as a green solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=2)=[O:8])[CH2:2]1.[CH2:37]([N:39](CC)CC)[CH3:38]>ClCCl.BrCC#N>[C:37]([CH2:38][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=2)=[O:8])[CH2:2]1)#[N:39]
Reactant: CCN(CC)CC
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCNC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: N#CCBr
Solvent: ClCCl
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCN(CC#N)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Yield: 45 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-pyrrolidin-3-ylamide from Step 1 was dissolved in dichloromethane with the addition of triethylamine and bromo-acetonitrile. The reaction was concentrated and dried from mixtures of dichloromethane and hexanes. The crude was dissolved in a mixture dichloromethane, tetrahydrofuran, and methanol, supported on silica gel and purified by flash chromatography (4 g silicycle) with 0% to 10% MeOH in dichloromethane (0.5% Et3N). The appropriate fractions were combined and concentrated. The solid obtained was triturated with Et2O and hexanes. The solid was discarded and the mother liquor was concentrated to afford 220 mg (45%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amide as a white solid, 220 mg (45% yield). LC-MS (M+H)+=549.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[CH2:10][C@H:9]1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:39]=[CH:38][C:29]([O:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:22](=[O:23])[NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:38]=[CH:39][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:37][CH:36]=3)[CH2:10]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluoro-2-methylbenzyl)pyrrolidine-2-carboxylic acid (540 mg, 1.54 mmol), prepared as in Reference 4, 4-(4-fluorophenoxy)aniline (313 mg, 1.54 mmol), DIEA (0.4 mL) and HATU (586 mg, 1.54 mmol) in DMF (3 mL) was stirred at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (20 mL) and then brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Product was purified from the residue by flash column (eluted with a 3:1 hexanes/ethyl acetate mixture) to give (2S,4R)-tert-butyl 4-(4-fluoro-2-methylbenzyl)-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate (826 mg, 1.59 mmol, 103%) as a reddish oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:19]=2)=[CH:11][C:10]=1[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>ClCCl>[O:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[C:10]1[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)nn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cn(C3CCNCC3)nn2)cc1-c1nc2ccccc2o1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
TFA (0.771 ml) was added to a stirred suspension of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]triazol-1-yl]piperidine-1-carboxylate (231 mg) dissolved in dichloromethane (5 ml) at room temperature. The resulting solution was stirred for 2 hours. Excess TFA was removed by azeotropic concentration with toluene. The residue was taken off with dichloromethane-methanol and treated with methanolic ammonia (7 M). The mixture was concentrated to dryness and the resulting solid was triturated with diethyl ether. The resultant solid was collected by filtration, washed with diethyl ether followed by petroleum ether and dried under vacuum at 60° C. to give 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)triazol-4-yl]pyridin-2-amine (180 mg) as a solid; NMR Spectrum: (DMSOd6+TFAd) 2.20-2.32 (m, 2H), 2.38-2.48 (m, 2H), 3.7-3.30 (m, 2H), 3.47-3.58 (m, 2H), 4.92-5.02 (m, 1H), 7.54 (ddd, 1H), 7.59 (ddd, 1H), 7.90 (d, 1H), 7.95 (dd, 1H), 8.84 (d, 1H), 8.96 (s, 1H), 9.24 (d, 1H); Mass spectrum: M+H+: 362
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([OH:18])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:29][C:30]1([C:41]([O:43][CH3:44])=[O:42])[CH2:35][CH2:34][C:33]([O:39][CH3:40])([CH2:36][O:37][CH3:38])[CH2:32][CH2:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([NH:29][C:30]3([C:41]([O:43][CH3:44])=[O:42])[CH2:31][CH2:32][C:33]([O:39][CH3:40])([CH2:36][O:37][CH3:38])[CH2:34][CH2:35]3)=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)O
Reactant: COCC1(OC)CCC(N)(C(=O)OC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: COCC1(OC)CCC(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)(C(=O)OC)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
574 mg (2.20 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) were dissolved in 0.9 g (12.5 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for 1 h and then concentrated. The residue was dissolved in 5 ml of acetonitrile. 816 mg (5.90 mmol) of potassium carbonate were added to 390 mg (1.69 mmol) of the compound from Example 24A in 10 ml of acetonitrile. With ice-cooling, the solution of the acid chloride was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was then concentrated, the residue was taken up in ice-water and extracted repeatedly with dichloromethane, and the combined organic phases were washed repeatedly with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. This gave 570 mg of the title compound as a diastereomer mixture which were reacted without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH2:10][O:11][CH2:12][O:13][CH3:14].[H-].[Na+]>CN(C=O)C>[CH3:14][O:13][CH2:12][O:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ncc[nH]1
Reactant: COCOCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOCCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 79.5 %

Procedure:
In DMF (15 ml), 2-imidazole carboxaldehyde (300 mg) was dissolved. Then, the compound (1.01 g) obtained in Example 92-1 and sodium hydride (137 mg) were added to the solution, and the whole was stirred at room temperature for 5 days. After completion of the reaction, the solvent was distilled off and the residue was then added with chloroform, followed by washing with water and saturated saline solution. The resultant was dried with anhydrous sodium sulfate, and the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (457 mg) as a yellow viscous liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([NH2:11])=[S:10])[CH:2]=1.[C:12]([CH2:14][C:15](OCC)=[O:16])#[N:13]>>[NH2:13][C:12]1[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:9](=[S:10])[NH:11][C:15](=[O:16])[CH:14]=1
Reactant: CCOC(=O)CC#N
Reactant: NC(=S)NCc1cccnc1
Product: Nc1cc(=O)[nH]c(=S)n1Cc1cccnc1
Yield: 82.7 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 1(b) using N-(pyridin-3-ylmethyl)thiourea (Beaudegnies, R., Wendeborm, S., Heterocycles, 2003, 11, 2417-2424) (1.19 g, 7.12 mmol) and ethyl cyanoacetate (0.97 g, 8.54 mmol), giving the title compound (1.38 g, 83%) as a solid.
Reaction SMILES: Cl[C@@H:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:3].[NH2:12][C:13]1[S:14][C:15]2[C:20]([NH:21][C@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])=[N:19][C:18]([SH:29])=[N:17][C:16]=2[N:30]=1>>[NH2:12][C:13]1[S:14][C:15]2[C:20]([NH:21][C@@H:22]([CH2:23][OH:24])[CH2:25][CH:26]([CH3:27])[CH3:28])=[N:19][C:18]([S:29][C@H:2]([C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=3)[C:7]#[N:8])[CH3:3])=[N:17][C:16]=2[N:30]=1
Reactant: C[C@@H](Cl)c1cc(C#N)ccn1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2cc(C#N)ccn2)nc2nc(N)sc12
Yield: 20.2 %

Procedure:
The title compound was prepared according to General Method A starting from 2-((R)-1-chloro-ethyl)-isonicotinonitrile (46 mg, 0.28 mmol) and (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (69 mg, 0.23 mmol). Purification by chiral HPLC (Column: Chiralpak AD 50×150 mm, eluent: heptane:isopropanol 85:15), flowrate 60 ml/min) yielded the title compound (20 mg, 20% yield).
Reaction SMILES: [F:1]/[C:2](=[C:8](/[CH3:19])\[CH:9]=[CH:10]\[C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[O:13][C:12]=1[CH3:18])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[F:1]/[C:2](/[C:8](/[CH3:19])=[CH:9]/[CH2:10][C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[O:13][C:12]=1[CH3:18])=[CH:3]\[OH:4]
Reactant: CCOC(=O)/C(F)=C(C)/C=C/c1c(C)oc(C)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCOCC
Product: CC(=C\Cc1c(C)oc(C)c1C)/C(F)=C/O
Temperature: -45 °C

Procedure:
A solution of crude ethyl 2Z,4E-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-furyl)pentadienoate in ether was stirred under argon and cooled to -45° C. Diisobutylaluminum hydride (DIBAH) (112 mmol) was added slowly until no starting material remained. Five ml. of a saturated solution of sodium sulfate was added at -10° C. and the mixture was allowed to warm to 30° C. for a completion of hydrolysis. Filtration through Celite and evaporation gave 12 g. of 2Z,4E-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-furyl)pentadien-1-ol which was carried on to the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][NH:7][C@@H:6]([CH3:9])[CH2:5][N:4]1[C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[O:20][CH2:19][C:18]1[N:13]2[C@H:14]([CH3:32])[C:15](=[O:31])[NH:16][N:17]=1.C=O.[BH3-][C:36]#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:31])[C@H:14]3[CH3:32])=[CH:11][C:10]=1[N:4]1[CH2:5][C@H:6]([CH3:9])[N:7]([CH3:36])[CH2:8][C@H:3]1[CH3:2]
Reactant: C[C@@H]1CN[C@@H](C)CN1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(C)[C@@H](C)CN1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of (R)-6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride (0.040 g, 0.094 mmol) in AcOH (1 mL) and MeOH (10 mL) was added paraformaldehyde (0.028 g, 0.945 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. NaBH3CN (0.015 g, 0.236 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. Aqueous saturated NaHCO3 solution (10 mL) was added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 20% MeOH in EtOAc) to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-((2R,5S)-2,4,5-trimethyl-piperazin-1-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.011 g, 60%). 1H NMR (400 MHz, CD3OD): δ 7.33-7.41 (m, 1H), 7.18-7.29 (m, 2H), 7.14 (m, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 4.58-4.69 (m, 3H), 3.18 (m, 2H), 2.96 (m, 1H), 2.71 (m, 2H), 2.59 (m, 3H), 2.27 (m, 1H), 1.48 (d, J=6.5 Hz, 3H), 1.15 (d, J=4.8 Hz, 3H), 0.75 (d, J=6.0 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.708 min.; MS m/z: 439 [M+H]+. SFC (Table 1, Method 56), Rt=2.337 min.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:7]1[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(Cl)Cl.O>CCCCCCCC>[CH2:12]([C:11]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(O)(CCCCCCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCC1(CCCCCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (9.38 mL) was added dropwise to 9-([2,2′-bithiophen]-3-yl)heptadecan-9-ol (IIe) (6.20 g, 15 mmol) in 200 ml n-octane under stirring at room temperature. After stirring for 12 h, CH2Cl2 (130 mL) and water (130 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ie) (3.19 g, 52.9%). 1H-NMR (CDCl3): δ=7.14 (d, J=4.8 Hz, 2H), 6.93 (d, J=5.1 Hz, 2H), 1.87-1.79 (m, 4H), 1.40-1.06 (m, 24H), 0.95-0.82 (m, 6H).