Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[CH3:8][N:9]=[C:10]=[S:11]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:10]([NH:9][CH3:8])=[S:11])[N:4]=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: CN=C=S
Solvent: CN(C)C=O
Product: CNC(=S)n1nc(C)nc1N
Yield: 29 %

Procedure:
The synthesis method of Example 1-(3) was applied. The compound (664 mg) obtained in (2) above, dimethylformamide (13 ml) and methyl isothiocyanate (600 mg) were used as reagents to give 340 mg of white crystals (yield 29%).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:45])[CH2:42][CH:43]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:40][CH:41]([CH3:45])[CH2:42][CH2:43][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CCN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 44.6 %

Procedure:
The product from Example 31D (80 mg, 0.141 mmol), 3-methylbutanal (18 μl, 0.170 mmol), acetic acid (10 μl, 0.166 mmol), and sodium triacetoxyborohydride (48 mg, 0.226 mmol) were processed as described in Example 27 to provide the title compound (40 mg, 45%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.78 (s, 2H), 7.32-7.11 (m, 10H), 5.32-5.08 (m, 6H), 3.95 (br s, 2H), 2.83 (br s, 2H), 2.71 (dd, 2H), 2.48-2.23 (m, 4H), 1.43 (m, 2H), 1.08 (m, 2H), 0.76 (t, 6H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.23 mL) was added to a solution of [5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 102-(1); 39.5 mg, 0.0762 mmol) in methanol (1.3 mL), and the mixture was stirred for two hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (8% methanol/dichloromethane) to give the title compound (21.6 mg, 56%).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-p-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([Cl:12])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CCOCC1

Procedure:
The tetrahydropyran-4-carboxylic esters II required for the novel reaction can be obtained from diethyl tetrahydropyran-4,4-dicarboxylate (i. Chem. Soc. (1952), page 2268). The tetrahydropyran-4-carboxylic esters of the formula II can be obtained from the diethyl ester by hydrolysis using potassium hydroxide to give tetrahydropyran-4,4-dicarboxylic acid, subsequent thermal decarboxylation to give tetrahydropyran-4-carboxylic acid, subsequent reaction with thionyl chloride to give tetrahydropyran-4-carbonyl chloride and subsequent esterification with alcohols (J. Chem. Soc. (1930), p. 2525).
Reaction SMILES: B#B.[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[CH:7][C:8]2[O:15][C:12]3([CH2:14][CH2:13]3)[C:11](=O)[NH:10][C:9]=2[CH:17]=1.O>O1CCCC1>[F:19][C:4]([F:3])([F:18])[C:5]1[CH:6]=[CH:7][C:8]2[O:15][C:12]3([CH2:13][CH2:14]3)[CH2:11][NH:10][C:9]=2[CH:17]=1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2OC12CC2
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)NCC1(CC1)O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Under ice cooling, 1.1 ml of a 1M solution of diborane in tetrahydrofuran were added dropwise to a solution of 1.07 g of 3,4-dihydro-6-trifluoromethyl-3-oxo-2H-1,4-benzoxazine-2-spiro-cyclopropane in tetrahydrofuran, followed by stirring at room temperature for 4 hours. The reaction mixture was ice cooled, to which iced water was added, followed by stirring at room temperature for 15 minutes. The reaction mixture was extracted with ethyl ether and the extract was dried over magnesium sulfate. The ethyl ether was distilled off and the residue was purified by chromatography on a silica gel column, whereby 0.96 g of the title compound was obtained (yield: 95%).
Reaction SMILES: C(O[C:9]([C:11]1[CH:16]=[CH:15][C:14](CO[Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=1)=[CH2:10])C1C=CC=CC=1.[CH2:26]([O:33]C(C1C=CC=C(CO[Si](C(C)(C)C)(C)C)C=1)=C)C1C=CC=CC=1.COC(C1C=CC(COC(C2C=CC=CC=2)=C)=CC=1)=O.ClCC=CC1C=CC=CC=1.[Si](Cl)(C(C)(C)C)(C)C.C>>[OH:33][CH2:26][CH:10]=[CH:9][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(OCc1ccccc1)c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: C=C(OCc1ccccc1)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: C
Agent: C=C(OCc1ccc(C(=O)OC)cc1)c1ccccc1
Agent: CC(C)(C)[Si](C)(C)Cl
Product: OCC=Cc1ccccc1

Procedure:
α-Benzyloxy[4-(tert-butyldimethylsilyloxymethyl)styrene] and α-Benzyloxy[3-(tert-butyldimethylsilyloxymethyl)styrene)] (Formula II, R1 =(tert-butyldimethylsilyloxymethyl)phenyl, R2 =benzyl). (Hydroxymethyl)styrene was prepared from (chloromethyl)styrene (a 2:3 mixture of para and meta isomers) by a sequence described in Polymer, 1973, 14, 330. It was treated with tert-butyldimethylsilyl chloride following the general directions found in Journal of the American Chemical Society, 1972, 94, 6190. Method C was used to convert the resulting compound to the required alkoxystyrene: 1H NMR (CCl4) δ 0.70 (6H, s), 0.94 (9H, s), 4.17 (1H, d, J 2.4 Hz), 4.63 (3H, broadened s), 4.83 (2H, s), 7.0-7.6 (9H, m); MS (CH4) 355 (MH+, 4%), 91 (100%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:6]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][C:11]1[O:10][N:9]=[C:8]([CH2:7][N:5]2[CH:6]=[C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:3]=[N:4]2)[CH:12]=1
Reactant: Cc1cc(Cn2cc(I)cn2)no1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1cc(Cn2cc(C#C[Si](C)(C)C)cn2)no1
Temperature: 60 °C

Procedure:
3-((4-Iodo-1H-pyrazol-1-yl)methyl)-5-methylisoxazole (30) (0.7 g, 2.42 mmol) and trimethylsilylacetylene (0.326 g, 3.32 mmol) were dissolved in DMF (5 ml) and placed under argon. Diisopropylamine (0.47 ml, 3.3 mmol), copper(I) iodide (30 mg, 0.16 mmol), triphenylphosphine (126 mg, 0.242 mmol) and palladium acetate (40 mg, 0.16 mmol) were added and the flask was flushed with argon. The reaction was heated at 60° C. for 1 hour. It was cooled to room temperature and diluted with water (20 ml) and ethyl acetate (30 ml). The organic layer was collected, dried and concentrated. The crude product was purified by flash silica chromatography eluting with 5% ethyl acetate in DCM. The pure fractions provided the title compound as a brown oil which solidified on standing (550 mg, 88%). 1H-NMR (500 MHz, CDCl3): 0.21 (s, 9H), 2.38 (s, 3H), 5.29 (s, 2H), 5.88 (s, 1H), 7.58 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[NH:3]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1>CC(N(C)C)=O.[Cu]=O>[C:15]([C:14]1[CH:13]=[C:12]([C:5]2([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[N:3]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=3)[C:2](=[O:1])[NH:6]2)[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: C=CCOCC1(c2cccc(C#N)c2)NC(=O)NC1=O
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Agent: O=[Cu]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2cccc(C#N)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 579 mg of 3-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 534 mg of 4-bromo-2-(trifluoromethyl)benzonitrile in DMAC (2.5 mL), 183 mg of copper oxide are added. The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in DCM, washed with a solution of 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:15]([CH3:28])[C:16]3[N:20]([CH3:21])[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:18][N:17]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:28][N:15]([C:16]1[N:20]([CH3:21])[C:19]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[N:18][N:17]=1)[CH:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:29]#[N:30])[N:9]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(c1nnn(-c2cccc(I)c2)n1)N(C)c1nnc(-c2ccncc2)n1C
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1nnn(-c2cccc(C#N)c2)n1)N(C)c1nnc(-c2ccncc2)n1C

Procedure:
The title compound is prepared from {1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[CH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([S:22]([OH:24])=[O:23])=[CH:18][CH:17]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][CH:15]=1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C(CC(=O)C(C)(C)C)c2ccc(Cl)cc2)cc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of 3 g of 4-chlorobenzalpinacolone, 2 g of p-toluenesulfinic acid and 15 ml of ethanol was refluxed for 8 hours and then allowed to stand at a room temperature overnight. The collection of the precipitated crystals gave 4.8 g of the captioned compound (yield: 94%). m.p. 170°-171° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:17]([C:19]1[CH:52]=[CH:51][C:22]([C:23]([CH2:25][NH:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([O:35][C:36](=[O:50])[NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:31][CH2:30]2)=[O:24])=[CH:21][CH:20]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C)C.C(O)(=O)C>[C:5]([CH:4]1[CH2:8][CH2:9][N:1]([CH2:17][C:19]2[CH:20]=[CH:21][C:22]([C:23]([CH2:25][NH:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36](=[O:50])[NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:31][CH2:30]3)=[O:24])=[CH:51][CH:52]=2)[CH2:2][CH2:3]1)(=[O:6])[NH2:7]
Reactant: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: NC(=O)C1CCN(Cc2ccc(C(=O)CNCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and isopropanol (400 mL). The reaction mixture was cooled to 0-10° C. with an ice bath and a solution of biphenyl-2-ylcarbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester (11 g, 22.7 mmol; prepared as described in Preparation 5) in isopropanol (300 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10° C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with 1N HCl (200 mL) to pH 3. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3×250 mL). The aqueous phase was then cooled to 0-5° C. with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10. This mixture was then extracted with isopropyl acetate (3×300 mL) and the combined organic layers were washed with water (100 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield. MS m/z: [M+H+] calc'd for C35H43N5O4 598.3; found 598.6. Rf=2.32 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH:19]2[CH2:21][CH2:20]2)O)=[CH:11][CH:10]=1.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2.[Cl-].[NH4+]>ClCCl>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([C:30]2[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=2)[CH:19]2[CH2:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC1(C2CC2)CCc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C3(C4CC4)CCc4ccc(Cl)cc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
0.03 ml (0.40 mmol) of trifluoroacetic acid was added to 70.0 mg (0.34 mmol) of the compound from Example 119A and 65.4 mg (0.37 mmol) of the compound from Example 8A in 1.6 ml of dichloromethane at 0° C., and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 52.4 mg (42% of theory) of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1>C(Cl)(Cl)Cl>[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:5](=[O:7])[CH3:6])=[C:11]([CH3:16])[CH:10]=1
Reactant: Cc1cc(F)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(F)cc1C
Yield: 99.8 %

Procedure:
Acetic anhydride (17.7 ml, 0.19 mol) was dropwise added to 4-fluoro-2-methylaniline (234 g, 0.19 mol). The solidified reaction mixture was dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was dried with a vacuum pump to obtain the entitled compound (31.7 g, 99%) as a pale red solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]([NH:28][C@@H:29]3[CH2:33][CH2:32][N:31]([C:34]4[N:42]=[C:41]5[C:37]([N:38]=[CH:39][N:40]5[C@@H:43]5[CH2:47][C@H:46]([N:48]6[CH:52]=[C:51]([CH2:53][OH:54])[CH:50]=[N:49]6)[C@@H:45]([OH:55])[C@H:44]5[OH:56])=[C:36]([NH:57][CH2:58][CH:59]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)[C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[N:35]=4)[CH2:30]3)=[O:27])[CH2:21][CH2:20]2)=[N:17][CH:18]=1)=[O:12])C.[OH-].[Li+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:56][C@@H:44]1[C@H:45]([OH:55])[C@@H:46]([N:48]2[CH:52]=[C:51]([CH2:53][OH:54])[CH:50]=[N:49]2)[CH2:47][C@H:43]1[N:40]1[CH:39]=[N:38][C:37]2[C:41]1=[N:42][C:34]([N:31]1[CH2:32][CH2:33][C@@H:29]([NH:28][C:26](=[O:27])[NH:25][CH:22]3[CH2:21][CH2:20][N:19]([C:16]4[CH:15]=[CH:14][C:13]([C:11]([OH:12])=[O:10])=[CH:18][N:17]=4)[CH2:24][CH2:23]3)[CH2:30]1)=[N:35][C:36]=2[NH:57][CH2:58][CH:59]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)N[C@@H]3CCN(c4nc(NCC(c5ccccc5)c5ccccc5)c5ncn([C@@H]6C[C@H](n7cc(CO)cn7)[C@@H](O)[C@H]6O)c5n4)C3)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NC1CCN(c2ccc(C(=O)O)cn2)CC1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(3-{(R)-1-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-ureido)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid ethyl ester trifluoroacetate (Example 79) (23 mg, 0.023 mmol) is dissolved in methanol (2 ml). Aqueous lithium hydroxide (6 mg, 0.23 mmol) is added and the reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo. The title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water—0.1% TFA). MS (ES+) m/e 422 (MH+/2).
Reaction SMILES: C(OC(=O)[N:7]([CH:20]1[CH2:23][N:22]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:21]1)[CH2:8][C@H:9]([OH:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([N:22]2[CH2:21][CH:20]([NH:7][CH2:8][C@H:9]([OH:19])[CH2:10][O:11][C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[CH2:23]2)(=[O:25])=[O:26])=[CH:32][CH:31]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(N(C[C@H](O)COc3ccc(O)cc3)C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOc1ccc(S(=O)(=O)N2CC(NC[C@H](O)COc3ccc(O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111 %

Procedure:
To a solution of [1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propyl]-carbamic acid tert-butyl ester (0.11 g, 0.2 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.15 ml, 2 mmol). The mixture was stirred at room temperature for 2 h, and then quenched with saturated sodium carbonate solution and extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sufate, and evaporated to give 0.10 g of a white solid; m.p. 55-58° C.; MS (ES) m/z 451 (MH+); HRMS (Cl) Calcd. for C22H31N2O6S (MH+): 451.1903, Found: 451.1882.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([O:17][CH2:18][C:19]3[N:23]=[CH:22][N:21]([CH3:24])[N:20]=3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:5]2=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)CCC>CN(C=O)C>[CH3:24][N:21]1[CH:22]=[N:23][C:19]([CH2:18][O:17][C:8]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:5]3[N:6]([C:2]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[N:3][N:4]=3)[N:7]=2)=[N:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cn1cnc(COc2nn3c(Br)nnc3cc2N2CCOCC2)n1
Solvent: CN(C)C=O
Product: Cn1cnc(COc2nn3c(-c4cccs4)nnc3cc2N2CCOCC2)n1
Temperature: 100 °C
Yield: 60.2 %

Procedure:
A mixture of 3-bromo-6-(1-methyl-1 H-1,2,4-triazol-3-ylmethoxy)-7-(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.25 mmol) and 2-(tributylstannyl)thiophene (240 mL 0.75 mmol) in dry DMF (3 ml) was deoxygenated by bubbling through nitrogen gas for 15 minutes. Dichlorobis(triphenylphosphine)palladium (II) (20 mg) was then added. The whole apparatus was further deoxygenated by three ‘evacuate/fill N2’ cycles. The mixture was then stirred and heated at 100° C. for 16 hours under nitrogen. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. Residual DMF was removed under high vacuum. The residue was purified by chromatography on silica gel, eluting with 5% methanol/dichloromethane to give the title compound (60 mg, 60%). Data for the title compound: 1H NMR (360 MHz, CDCl3) δ3.26-3.29 (4 H, m), 3.85-3.89 (4 H, m), 3.94 (3 H,-s), 5.64 (2 H, s), 7.19-7.23 (2 H, m), 7.47-7.59 (1 H, m), 8.05 (1 H, s), 8.18-8.20 (1 H, m); MS (ES+) m/e 399 [MH+]. Anal. Found C, 50.84; H, 4.39; N, 27.35. C17H18N8O2S. 0.3(H2O) requires C, 50.56; H, 4.64; N, 27.75%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])#[N:4].BrCCO[Si]([C:23](C)([CH3:25])[CH3:24])(C)C>CN(C=O)C.CCOC(C)=O>[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH:23]([CH3:25])[CH3:24])[C:8]([O:10][CH3:11])=[O:9])#[N:4]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
To a suspension of NaH (0.39 g, 9.3 mmol) in DMF (15 mL) was added a solution of 3 (1.9 g, 6.5 mmol) in DMF (10 mL) at 0° C. under nitrogen. The reaction was stirred for 1.5 h, and then (2-bromoethoxy)-tert-butyldimethylsilane (2.09 mL, 9.7 mmol) was added. The reaction mixture was stirred overnight, diluted with EtOAc, quenched with aqueous ammonium chloride solution, and extracted with EtOAc (3×50 mL). The organic layers were combined and dried over Na2SO4. Purification with over silica gel (EtOAc) gave the product 4 (1.2 g, 41%) as a light yellow solid.