Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[N:18]=[N:19][C:20]([NH:23][NH2:24])=[CH:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.C([O-])([O-])=O.[Na+].[Na+].[N:31]#[C:32]Br>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]3[N:19]([C:32]([NH2:31])=[N:24][N:23]=3)[N:18]=1)[CH:14]=[CH:13][O:12]2
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)nn1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reaction time: 1 h
Yield: 57 %

Procedure:
The 6-(2,4-difluorophenyl)-5-(6-hydrazinylpyridazin-3-yl)imidazo[2,1-b]oxazole (0.300 g, 0.914 mmol, Example #40, Step B, was dissolved in MeOH (15 mL) at about ambient temperature before addition of Na2CO3 (0.112 g, 1.371 mmol). Cyanogen bromide (3M in DCM, 0.305 mL, 0.914 mmol) was added and the resulting mixture was stirred at about ambient temperature for about 1 h. The crude mixture was partitioned between water and DCM. The organics were dried over MgSO4, filtered, concentrated under reduced pressure to give a yellow solid that was triturated with Et2O and filtered to give the title compound (0.185 g, 57%): LC/MS (Table 1, Method g) Rt=1.65 min.; MS m/z: 354.07 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:23][O:24][C:25](=[O:42])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1)=[CH2:27]>C(Cl)Cl>[CH3:23][O:24][C:25](=[O:42])[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1)[CH2:27][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:12])=[O:13]
Reactant: C=C(C(=O)OC)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: O=[PH](O)CCCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(CP(=O)(O)CCCCc1ccccc1)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To 4-phenylbutylphosphinic acid (357 mg, 1.8 mmol) in methylene chloride at 0° C. was added DIEA (0.66 mL, 3.8 mmol), followed by TMSCI (0.47 mL, 3.8 mmol). After 1 hour, 2-(3-(t-butoxycarbonylamino)phenyl)propenoic acid methyl ester (0.5 g, 1.8 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 5 hours, the reaction was partitioned between methylene chloride and saturated NaHCO3 solution. The organic layer was washed with 0.1 N sulfuric acid and concentrated in vacuo. The residue was dissolved in 10 mL 3:1 THF:methanol for 18 hours. The reaction was concentrated to provide 2-(3-(t-butoxycarbonylamino)phenyl)-3-((4-phenylbutyl)(hydroxy)phosphinoyl)propanoic acid methyl ester (845 mg) as a white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Yield: 69.5 %

Procedure:
According to General Procedure A, a mixture of 4-chloroanisole (0.06 mL, 0.50 mmol), phenylboronic acid (91 mg, 0.75 mmol), CsF (228 mg, 1.50 mmol), Pd(OAc)2 (2 mg, 0.01 mmol) and 12f (8 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to reflux, cooled and filtered. Evaporation of the solvent under reduced pressure and column chromatography of the pre-adsorbed crude material (0.5-1.0% isopropanol/hexane, silica gel) gave 51e (64 mg, 70%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.54 (t, 4H, J=6.8 Hz), 7.42 (t, 2H, J=6.8 Hz), 7.32-7.26 (m, 1H), 6.99 (d, 2H, J=8.7 Hz), 3.86 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 159.1, 140.8, 133.8, 128.7, 128.1, 126.7, 126.6, 114.2, 55.3.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]2[O:7][C:8]([CH3:26])([CH3:25])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](OCC)=[O:20])=[CH:13][C:12]3=[O:24])[C:5]=2[CH:4]=1)#[N:2].[BH4-].[Na+].Cl>O1CCOCC1>[C:1]([C:3]1[CH:28]=[CH:27][C:6]2[O:7][C:8]([CH3:26])([CH3:25])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][C:12]3=[O:24])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCc1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C=C(n2ccc(CCCO)cc2=O)c2cc(C#N)ccc2O1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In 16 ml of dioxane, is dissolved 617 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(2-ethoxycarbonylethyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 33. Then, 16 ml of an aqueous solution containing 617 m of sodium borohydride is added at room temperature and reacted first at room temperature for 1.5 hours and then at 60° C. for one hour. After stopping the reaction by adding 20 ml of 2M aqueous hydrochloric acid, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/10 mixture of methanol/methylene chloride as a developing solvent. Thus, 493 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-(3-hydroxypropyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13]Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])O.[Na+].[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O>[C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: Sc1ccccc1
Reactant: O=C(N[C@@H](CCl)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
N-Carbobenzyloxy-β-chloro-L-alanine (0.091 g, 0.35 mmol) was dissolved in 0.45 ml of water and, then, 0.065 g (0.77 mmol) of sodium hydrogen carbonate was added. Thereafter, 0.046 g (0.42 mmol) of thiophenol was added dropwise at room temperature in a nitrogen gas atmosphere. After 2 hours of stirring at 60° C., the reaction mixture was cooled with ice and acidified with 1 N hydrochloric acid, and then extracted with ethyl acetate. The solvent was distilled off and the residue was purified by column chromatography to give 0.097 g (0.29mmol, 84%) of N-carbobenzyloxy-S-phenyl-L-cysteine. The product obtained had an optical purity of not less than 98% e.e. as determined by HPLC analysis following the same procedure as in Example 13.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19]>C(OC(=O)C)(=O)C.I>[OH:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COc1c(CC(=O)O)cccc1Oc1cccc(Cl)c1
Agent: I
Solvent: CC(=O)OC(C)=O
Product: O=C(O)Cc1cccc(Oc2cccc(Cl)c2)c1O
Yield: 48.3 %

Procedure:
A solution of 2-[2-methoxy-3-(3-chlorophenoxy)phenyl]acetic acid (10 g) in acetic anhydride (30 ml) and 48% hydriodic acid (60 ml) were treated in a similar manner to that of Example 6-(6) to give 2-[2-hydroxy-3-(3-chlorophenoxy)phenyl]acetic acid (4.6 g). mp 99°-102° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[H-].[Al+3].[H-].[H-].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:31]([N:33]([CH3:35])[CH3:34])=O)[C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.[OH-].[Na+]>C1COCC1.C1COCC1.O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:31][N:33]([CH3:35])[CH3:34])=[CH:21][CH:22]=1
Reactant: CN(C)C(=O)C(c1ccc(Br)cc1)C1(O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC(c1ccc(Br)cc1)C1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (0.7 g) was suspended in dry THF (25 ml) cooled to 0° C. and concentrated sulfuric acid (0.5 ml) cautiously added in an in situ preparation of aluminum hydride. The mixture was stirred for one hour at 0° C. and the amide, 1-[(4-bromophenyl)[dimethylaminocarbonyl]methyl]cyclohexanol (4 g, 0.012 mole) was dissolved in THF (35 ml) and added rapidly dropwise. The reaction mixture was stirred at 0° C. for one hour. A THF-water mixture (1:1 v/v 6 ml) was added slowly followed by 10% sodium hydroxide (10 ml). The mixture was filtered and the residue washed well with ethyl acetate. The combined filtrate was dried over anhydrous potassium carbonate and evaporated to an oil (3.5 g) which was converted to the hydrochloride salt using 4 N isopropanolic HCl.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:16]3[N:15]=[C:14]([N:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[CH:19]=[CH:18][N:17]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3nccc(N4CCC(N)CC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 starting {1-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester. The product is in the form of the hydrochloride.
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[CH3:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][NH:16][CH:15]=1)=[O:13].C1(N2CCC(OC3C=CC(I)=CC=3)CC2)CCC1.[C:37]([N:41]1[CH2:46][CH2:45][CH:44]([O:47][C:48]2[CH:53]=[CH:52][C:51](I)=[CH:50][CH:49]=2)[CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([N:41]1[CH2:42][CH2:43][CH:44]([O:47][C:48]2[CH:53]=[CH:52][C:51]([N:16]3[CH:17]=[CH:18][C:14]([C:12]([NH:11][CH3:10])=[O:13])=[CH:15]3)=[CH:50][CH:49]=2)[CH2:45][CH2:46]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)N1CCC(Oc2ccc(I)cc2)CC1
Reactant: CNC(=O)c1cc[nH]c1
Agent: Cn1ccc(C(=O)O)c1
Agent: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: CNC(=O)c1ccn(-c2ccc(OC3CCN(C(C)(C)C)CC3)cc2)c1

Procedure:
The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by N-methyl-1H-pyrrole-3-carboxamide and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 1-tert-butyl-4-(4-iodophenoxy)piperidine.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[N:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[S:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=3)=[CH:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[N:22][CH:21]=[CH:20][C:19]=2[NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[S:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=2)[N:24]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a slurry of sodium hydride (95%, 0.045 g, 1.8 mmol) in 10 mL anhydrous THF at 0° C. under an atmosphere of N2 was added diethyl malonate (0.32 g, 2.0 mmol) dropwise. The mixture was stirred for 30 minutes at ambient temperature, treated with the product from Example 24a (0.141 g, 0.3 mmol), heated at 110° C. for two hours, cooled and partitioned between EtOAc and water. The ethyl acetate layer washed with saturated brine, dried over sodium sulfate, filtered and concentrated giving the title compound as a yellow glass, (0.14 g, 84% yield).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=O.Cl.[Cl-].[Na+]>O1CCCC1.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[OH:4][CH2:5][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a stirred solution of zinc chloride (23.2 g) in anhydrous tetrahydrofuran (300 ml) at 0° C. is added sodium borohydride (13.8 g) and the mixture is allowed to warm to room temperature and is stirred overnight. To the mixture is added cis-(±)-4-(methoxycarbonyl)-3-[((phenylmethoxy) carbonyl)amino]-2-azetidinone (39.2 g) and the reaction mixture is slowly heated to 65° C. and stirred at that temperature for 2 hours. The reaction mixture is cooled to 0° C. and 6 N hydrochloric acid (200 ml) is added dropwise with stirring. The mixture is poured into ethyl acetate (1 1) and the organic layer is taken. The aqueous layer is saturated with sodium chloride and re-extracted with ethyl acetate (200 ml). The combined organic layer is washed with water (200 ml) and with 200 ml of brine twice and dried over anhydrous sodium sulfate. The solvent is concentrated under reduced pressure to afford a yellow oil which is purified by column chromatography on silica gel (ethyl acetate as eluent) to obtain 24.3 g of the title product. Physical characteristics are as follows: m.p. 98°-100° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[Cl:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[Cl:19][C:20]1[CH:27]=[C:26]([O:28][CH2:2][C:3]2[C:4]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:5][O:6][C:7]=2[CH:8]([CH3:10])[CH3:9])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(C=O)c(Cl)c1

Procedure:
A mixture of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (1 g, 3.28 mmol), 2-chloro-4-hydroxybenzaldehyde (498 mg, 3.18 mmol), potassium carbonate (431 mg, 3.12 mmol), sodium iodide (98 mg, 0.66 mmol) in acetone (20 mL) was refluxed for 5 h. The reaction was concentrated and the residue was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and condensed to a residue which was chromatographed on silica gel eluting with 200% ethyl acetate/hexanes. Yield=0.98 g (71%) of 2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:10][CH2:11][C:12]1([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CS(C)=O>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:19][CH2:18][C:12]2([C:11]#[N:10])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: N#CC1(CN)CCOCC1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CS(C)=O
Product: N#CC1(CNc2cc(I)c(Cl)cn2)CCOCC1

Procedure:
A solution of 5-chloro-2-fluoro-4-iodopyridine (1 g, 3.88 mmol) and 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (1.634 g, 11.65 mmol) in 4 mL of dimethylsulfoxide was heated at 100° C. for 8 hours. The mixture was quenched with 100 mL of ice-cold water and was extracted with ethyl acetate (50 mL×2). The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 20% ethyl acetate in hexane) afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16]C=C[N:13]=3)=[N:11][C:7]=2[CH:6]=1.[NH:36]1C=CC(C=O)=N1>>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][NH:36][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2F)cn1
Reactant: O=Cc1cc[nH]n1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cc[nH]n4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 202 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 223 and 1H-pyrazole-3-carboxaldehyde.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][N:8]=1.[CH3:15][C:16](N(C)C)=[O:17]>C1COCC1>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:16](=[O:17])[CH3:15])[N:12]=1
Reactant: COc1ccnc(I)n1
Reactant: CC(=O)N(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccnc(C(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
A solution of isopropylmagnesium chloride (4.2 mmol) in THF (2.0M, 2.1 ml) was added dropwise to a stirred solution of 2-iodo-4-methoxypyrimidine (prepared according to Leprete et al. in Tetrahedron, 2000, 56, 265-273) (1.0 g, 4.2 mmol) in THF (12 ml) at 0° C. under N2. The reaction was stirred for 30 min at 0° C. and then DMA (409 μl, 4.4 mmol) was added. The reaction was stirred for 1 h and then quenched by addition of NH4Cl solution (15 ml) and extracted with EtOAc (50 ml and 20 ml). The combined organics were concentrated under reduced pressure and purified by column chromatography on silica, using 75% Et2O/iso-hexanes as eluent, to yield 1-(4-methoxypyrimidin-2-yl)ethanone (206 mg, 32%): 1H NMR (360 MHz, CDCl3) δ 8.59 (1H, d, J 5.7), 6.83 (1H, d, J 5.7), 4.08 (3H, s), 2.74 (3H, s); m/z (ES+) 153 (M+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N#N>C1COCC1.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:18][CH:19]=1)[CH2:11][CH2:12][CH3:13]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of p-bromobenzaldehyde (50 g, 270 mmol), 1-butyl-4-ethynylbenzene (47.0 g, 297 mmol), Et3N (540 mmol, 75 mL), CuI (0.52 g, 2.70 mmol), and PPh3 (1.42 g, 5.40 mmol) in 500 mL dry THF was degassed for 15 min by passing a stream of N2 through the solution. Pd(OAc)2 (1.21 g, 5.40 mmol) was then added and the black solution was stirred at rt for 17 hours. 1-butyl-4-ethynylbenzene (4.3 g) was added and the reaction stirred for an additional 3 hours. The reaction was filtered and 20 g of activated charcoal was added to the combined filtrates. This suspension was stirred for 2 hours at rt and was filtered over a pad of celite and reduced to a dark brown solid. The solid was taken up in DCM and added 100 g silica gel and removed the solvent. The product, now disposed on silica gel, was added to the top of a silica gel plug, preconditioned with 5% EtOAc in c-Hex, and filtered using 5% EtOAc in c-Hex, then up to 50%. The fractions containing the product were concentrated to a dark solid. The solid was taken up in 500 mL EtOAc and reduced to half volume. The solution was allowed to stand at rt and solids appeared. Then 200 mL pentane was added and cooled to 0° C. This was allowed to stand overnight. The solids were filtered and washed with 10% MTBE in pentane. The solids were still very dark. This material was further purified by flash chromatography on SiO2 (10/90 EtOAc/c-Hex). The combined pure fractions were evaporated to give a light brown solid. This solid was crystallized by dissolving in 100/150 EtOAc/MTBE with slight heating. Upon cooling to rt, solids appeared. 400 mL of pentane were added and the resulting mixture was then cooled to 0° C. and allowed to stand overnight. The solids were filtered and washed with 750 mL 1/3 MTBE/Pentane to give the title compound as a slightly off-white colored solids (a plate like crystal) (41.0 g, 58%). 1H NMR (CDCl3) δ: 10.03 (s, 1H), 7.87 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 2.66 (t, J=7.9 Hz, 2H), 1.71-1.56 (m, 2H), 1.46-1.31 (m, 2H), 0.98 (t, J=7.2 Hz, 3H). HPLC, Rt: 5.3 min (purity: 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[C:11]([CH3:13])[CH:10]=[N+:9]2[O-])=[CH:4][CH:3]=1.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][C:10]1[C:11]([CH3:13])=[N:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c[n+]([O-])n(-c2ccc(F)cc2)n1
Product: CC(=O)Oc1nn(-c2ccc(F)cc2)nc1C

Procedure:
2-(4-Fluorophenyl)-4-methyl-2H-1,2,3-triazole 1-oxide (i.e. the product of Step A, 6.6 g, 34 mmol) was added to acetic anhydride (47 mL, 500 mmol), and the reaction mixture was stirred at reflux for 28 h. The reaction was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed successively with water and saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to afford the title compound (7.8 g) as a beige solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH3:43])[O:35][CH:34]([CH2:36][N:37]2[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]2)[CH2:33][O:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:31]1([CH3:43])[O:35][C@H:34]([CH2:36][N:37]2[CH:41]=[CH:40][C:39]([NH:42][C:27]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:12]([C:15]4[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=4)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]3)=[O:28])=[N:38]2)[CH2:33][O:32]1
Reactant: CC1(C)OCC(Cn2ccc(N)n2)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (59.14 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (91.2 mg, 74.68%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H45Cl2N5O2S+H [(M+H)+]: 610.2346. found: 610.2345.