Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH:7]=O.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].N1CCCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[C:9]([C:11](=[CH:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: Cc1nnsc1C=O
Reactant: CCOC(=O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1snnc1C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To 50 ml of toluene were added 1.5 g (12 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbaldehyde, 1.5 g (13 mmol) of ethyl cyanoacetate, 0.40 g (6.0 mmol) of pyrrolidine and 0.20 g (1.2 mmol) of tosylic acid. In a reactor equipped with a Dean-Stark dehydrating apparatus, the mixture obtained above was stirred for 2 hours with heating under reflux. After the reaction was completed, a saturated aqueous solution of sodium chloride was added to the reaction mixture, the objective product was extracted with ethyl acetate, the organic layer was washed successively with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.73 g of the objective compound was obtained.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][NH2:28].[Cl:30][C:31]1[CH:32]=[C:33]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:34][N:35]([CH3:46])[C:36]([C:38]1[CH2:39]N(C)[C:41](=[O:44])[C:42]=1[OH:43])=[O:37]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][N:28]1[CH2:39][C:38]([C:36](=[O:37])[N:35]([CH2:34][C:33]2[CH:47]=[CH:48][C:49]([Cl:50])=[C:31]([Cl:30])[CH:32]=2)[CH3:46])=[C:42]([OH:43])[C:41]1=[O:44]
Reactant: COC(=O)CCN
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: COC(=O)CCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 17 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and β-alanine methyl ester as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (34.3 mg, 17% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (m, 2H), 7.09 (m, 1H), 4.59 (s, 2H), 4.27 (s, 2H), 3.77 (m, 2H), 3.67 (s, 3H), 3.03 (s, 3H), 2.69 (t, 2H, J=6.22). HRMS (M+H) calcd for C17H19N2Cl2O5: 401.0671. found: 401.0669.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=4[F:37])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[F:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([F:37])[C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4c(F)cccc4F)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3c(F)cccc3F)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-(4-{2-[2-(2′,6′-difluoro-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the product as a solid. 1H NMR (400 MHz, CDCl3) δ8.05 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.34-7.28 (m, 1H), 7.02-6.98 (m, 2H), 6.91-6.78 (m, 4H), 4.17 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.39 (s, 3H), 1.53 (s, 6H); MS (EI) 494.5 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[C:8]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=3)=[CH:23][CH:22]=2)[CH2:17][CH2:18]1
Reactant: OB(O)c1ccc(OCC2CC2)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(OCC2CC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(cyclopropylmethoxy)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H18N4O, 331. Found, 331.
Reaction SMILES: [CH2:1]([C:3]([CH2:14][CH3:15])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[C:4]([NH2:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:14]([C:3]([CH2:1][CH3:2])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH2:6])=[O:5])[CH3:15]
Reactant: CCC(CC)(C(N)=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of α,α-diethyl-2-hydroxy-benzeneacetamide (Example 266b, 1.21 g) in DMF (9.93 mL) was treated with potassium carbonate (0.807 g) and benzyl bromide (0.694 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography eluting with 30-100% ethyl acetate in iso-hexane) to afford the subtitle product (0.77 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C1C=CC=CN=1)C.[C:39]1([CH3:49])[C:40]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:49][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45]([NH:48][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:5]=2)=[CH:10][CH:11]=1)=[O:16])(=[O:47])=[O:46]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1OC(C)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2)cc1OC(C)CCCc1ccccc1
Reaction time: 50 h
Yield: 103.4 %

Procedure:
To a solution of acid 4'-methoxy-3'-(1-methyl-4-phenylbutoxy)-(±)[1,1'-biphenyl]-4-carboxylic acid, (0.257 g, 0.658 mmoles) in 10 ml of anhydrous methylene chloride under hydrogen atmosphere was added dimethylamino pyridine (88.46 mg, 0.728 mmoles); o-Toluenesulfonamide (0.122 g, 0.712 mmoles) and dicyclohexylcarbodiimide (0.124 g, 0.6 mmoles) the reaction mixture allowed to stir for 50 hours. The solvent was evaporated and the resulting solid triturated with methylene chloride:ether (~1:1) which lead to precipitation of by-product DCU which was filtered. Concentration of the mother liquor followed by 3 g additional triturations with ethyl acetate/ether (~1:1) caused additional deposit of white solid which was filtered. The clear filtrate was concentrated and purified on a silica gel column using methylene chloride/methanol as eluant (95:5). Concentration of fractions containing desired products gave a total of 0.37 g of white foamy solid. Recrystallization from ethyl acetate/hexane gave 0.208 grams of white solid. M.P.: 97°-100° C.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A suspension of (R)-tert-butyl 2-(4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (6 g, 13.6 mmol), ammonium formate (12.8 g, 203 mmol) and Pd/C5% (721 mg, 0.339 mmol) in methanol (103 ml) was stirred at 60° C. for 2 h. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and water. The organic phase was extracted twice with 0.5M HCl. The combined aqueous phases were basified with 2M-NaOH and extracted twice with DCM. The organic phases were dried over magnesium sulfate, filtered and dried in vacuo, to yield 3.04 g off-white solid. MS (ISP): 279.1 ([M+H]+).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:18])[CH:7]=[C:8]([N:13]3[CH:17]=[N:16][N:15]=[CH:14]3)[CH:9]=2)[N:4]=1.[ClH:19]>>[ClH:19].[CH3:18][C:6]1[CH:7]=[C:8]([N:13]2[CH:14]=[N:15][N:16]=[CH:17]2)[CH:9]=[C:10]2[C:5]=1[NH:4][C:3](=[O:2])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(-n3cnnc3)cc(C)c2n1
Agent: Cl
Product: Cc1cc(-n2cnnc2)cc2ccc(=O)[nH]c12

Procedure:
The following compound, m.p.>350°, was prepared similarly to the previous Example, starting from 2-methoxy-8-methyl-6-(1,2,4-triazol-4-yl)-quinoline and 5M HCl, except that, after refluxing the methoxy starting material with 5M HCl and cooling, the hydrochloride 1/4 hydrate crystallised out of solution and was filtered off and dried. ##STR60##
Reaction SMILES: [CH3:1][C:2]([CH3:18])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[OH:17])=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:3][C:2]([CH3:18])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[O:17][S:27]([CH3:26])(=[O:29])=[O:28])=[O:6])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
Cis-1-[(1,1-Dimethylethoxy)carbonylamino]-2-hydroxyindan (Method 5; 14.0 g, 56.2 mmol) was dissolved in DCM (200 ml) and triethylamine (11.8 ml, 84.3 mmol). Methanesulfonyl chloride (7.1 g, 61.9 mmol) dissolved in DCM (20 ml) was added and the mixture stirred at room temperature for 3 hours. The mixture was evaporated and EtOAc (250 ml) added. After washing with water and drying over magnesium sulphate the organic solution was evaporated to yield Cis-1-[(1,1-dimethylethoxy)carbonylamino]-2-methanesulphonyloxyindan (9.7 g, 98%) as a white solid.
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH:10]([NH2:18])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(=[O:21])[CH3:20].[Na+].C(OC(=O)C)(=O)C>C(OCC)(=O)C.O>[C:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH:10]([NH:18][C:19](=[O:21])[CH3:20])[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: NC1Cc2ccccc2C(c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)NC1Cc2ccccc2C(c2ccccc2)C1
Reaction time: 24 h
Yield: 80.1 %

Procedure:
To a solution of 180 mg (0.80 mmol) of 4-phenyl-2-aminotetraline HCl in 3.5 ml ethyl acetate and 2.0 ml water, was added 360 mg of sodium acetate. To this mixture 0.6 ml of acetic anhydride was then added and the mixture was stirred for 24 hrs. The addition of 2 ml of water resulted in the formation of two layers. After separation, the water layer was extracted twice with ethyl acetate. The combined organic layers were washed 3 times with a saturated solution of sodium bicarbonate and once with a saturated solution of sodium chloride. After drying over magnesium sulfate, the organic solution was evaporated under reduced pressure to yield 4-phenyl-2-acetamidotetralin as a white solid (170 mg, 79%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[Cl:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:19])=[CH:11][C:10]=1[Cl:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CBr)cc1Cl
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a stirred and cooled (0° C.) solution of 4.00 g (14.1 mmol) of the product of Step B dissolved in 70 mL of CH2Cl2 was added 5.84 g (17.6 mmol) of carbon tetrabromide and 4.61 g (17.6 mmol) of triphenylphosphine. After the addition the reaction mixture was allowed to warm to room temperature and was stirred 3 hours. The mixture was then evaporated in vacuo and purified on a silica gel flash chromatography column eluted with 2% ethyl acetate/hexane to afford 4.50 g (92%) of the title compound.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1>O1CCOCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]([F:15])([F:16])[F:17])[C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cnc(Cl)cc1C(F)(F)F

Procedure:
9.6 g (0.047 mol) of methyl 4-trifluoromethylpyridin-3-ylcarboxylate, dissolved in 50 ml of dichloromethane, are treated with 30% hydrogen peroxide/urea adduct and 17 ml of trifluoroacetic anhydride. The reaction solution is stirred at temperature of 20° C. for 20 hours and then washed once each with dilute sodium hydroxide solution and half-saturated sodium chloride solution. The product obtained is 3-methoxycarbonyl4-trifluoromethyl-3-pyridine N-oxide; 1H NMR (CDCl3, ppm): 8.55, s, 1H; 8.31, d, 1H; 7.6, d, 1H; 3.98, s, 3H. 4.85 g (0.022 mol) of the above product are then added to a mixture of 5 ml of phosphorus oxychloride and 4.3 ml of ethyidiisopropylamine in 15 ml of 1,2dichloroethane, and the mixture is heated to a temperature of 60° C. After about 2 hours, another 2 ml of phosphorus oxychloride and 2.8 ml of ethyidiisopropylamine are added, and the mixture is stirred at this temperature for 20 hours. The reaction mixture is subsequently added to ice-water, adjusted to pH 3 using 30% NaOH and then extracted with dich ioromethane. Filtration through a little silica gel gives an approximately 5:1 product mixture of the two 6-chloro- and 2-chloro-4-trifluoromethylpyridin-3-yl methyl esters, which can be separated by HPLC into the pure components. Thus, pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the main product; 1H NMR (CDCl3, ppm): 8.91, s, 1H; 7.68, s, 1H; 3.98, s, 3H, and pure methyl 2-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the byproduct; 1H NMR (CDCl3, ppm): 8.64, d, 1H; 7.52, d, 1H; 4.01, s, 3H. In the presence of 0.073 g of potassium hydroxide, 0.22 g of pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate are hydrolysed at room temperature in a 1:1 mixture of 6 ml of dioxane/water. Recrystallization gives the pure 6-chloro-4-trifluoromethyinicotinic acid: m.p. 115-117° C.; 1H NMR (CDCl3, ppm): 9.12, s, 1H; 7.24, s, 1H.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[N:23][C:24]=4Cl)[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][NH2:37]>O1CCOCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[N:23][C:24]=4[NH:36][NH2:37])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C

Procedure:
To a microwave vial was added tert-butyl{1-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) (4.05 g, 8.34 mmol), anhydrous hydrazine (5.24 mL, 167 mmol), and 1,4-dioxane (15 mL). The reaction mixture was then heated under microwave irradiation for 5 minutes at 100° C. (high absorption). The reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl{1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) as an orange solid/foam. MS (M+H)+: observed=482.3, calculated=482.59.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl.C[O:20][C:21](=O)[C:22]([S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])([CH3:34])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][C:30]([CH3:32])=[C:29]([CH3:33])[CH2:28][CH2:27]1>ClCCl>[C:38]1([S:35]([C:22]([CH3:34])([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][C:30]([CH3:32])=[C:29]([CH3:33])[CH2:28][CH2:27]2)[CH2:21][OH:20])(=[O:36])=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COC(=O)C(C)(CCCN1CCC(C)=C(C)C1)S(=O)(=O)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1=C(C)CN(CCCC(C)(CO)S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of diisobutylaluminium hydride in toluene (1.0M, 6 ml, 0.6 mmol) was added to a stirred solution of 2-benzenesulfonyl-5-(4,5-dimethyl-3,6-dihydro-2H-pyridin-1-yl)-2-methyl-pentanoic acid methyl ester hydrochloride (60 mg, 0.15 mmol) in dichloromethane at 5° C. The mixture was stirred for 30 min., diluted with dichloromethane (15 ml) and quenched with water (3 drops). The resulting mixture was stirred for 30 min. and solid Na2SO4 was added. The mixture was filtered through a pad of Celite and concentrated. The residue was purified on silica gel (dichloromethane:methanol) to give the title product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[C:24](Cl)(=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[CH2:17]([NH:16][C:14]([C:4]1[S:3][C:2]([NH:1][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:6][C:5]=1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of 2-amino-N,4-dibenzylthiazole-5-carboxamide (0.053 g, 0.16 mmol) in tetrahydrofuran (5 mL) at 0° C. was added hydrocinnamoyl chloride (0.03 mL, 0.20 mmol), DMAP (cat.) and triethylamine (0.3 mL, 2.10 mmol). The reaction mixture was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford the title compound in 49% yield (0.036 g); 1H NMR (CDCl3, 400 MHz) δ 7.35-7.15 (m, 15H), 4.56 (d, J=5.6 Hz, 2H), 4.37 (s, 2H), 3.03 (t, J=7.6 Hz, 2H), 2.74 (t, J=7.6 Hz, 2H); MS (ES+) m/z 456 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][O:8][CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: N=C(NO)c1ccc(Br)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CONC(=N)c1ccc(Br)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of 4-Bromo-2-fluoro-N-hydroxybenzimidamide 24 (800 g, 3.43 mol, 1 eq) and Amberlyst® A21 (20 wt %, 160 g) in PhMe (12 L, 15 vol) was added ethyl propiolate (471 g, 4.8 mol, 1.4 eq) at 10° C. The reaction was stirred at 50° C. overnight and checked by LC-MS (ca 14A % of starting material 24 was left). Reaction was then filtered and the filtrate was concentrated under vacuum, and 1015 g ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 was obtained as a yellow oil with 84.9% LC purity (yield: 89%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8][OH:9])[CH2:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[C:23]([CH2:24][CH:25]=O)=[C:22](Cl)[N:21]=[CH:20][N:19]=1>CC(O)C>[Cl:17][C:18]1[C:23]2[CH:24]=[CH:25][N:1]([C@H:2]3[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8][OH:9])[CH2:3]3)[C:22]=2[N:21]=[CH:20][N:19]=1
Reactant: N[C@@H]1C[C@@H](CO)[C@@H](O)C1
Reactant: O=CCc1c(Cl)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC[C@@H]1C[C@@H](n2ccc3c(Cl)ncnc32)C[C@@H]1O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (250 mg, 1.90 mmol) and triethylamine (380 mg, 3.80 mmol) in 2-propanol (30 mL) was treated with 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (330 mg, 1.71 mmol) at 80° C. The reaction was monitored by HPLC and all aldehyde was found to have been consumed after 19 h. The reaction mixture was cooled to ambient temperature. Approximately 80% of the solvent was removed under reduced pressure and the resulting brown solution was added with stirring to water (30 mL). The resulting clear solution was cooled in an ice-water bath resulting in product crystallization. The resulting slurry was stirred at less than 5° C. for thirty minutes and filtered. The filter cake was washed with cold water (10 mL) and dried in a vacuum oven at 40° C. for 14 h to obtain the title compound as a brown solid (311 mg, 68% yield). 1H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 7.68 (d, J=3.7 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 5.54 (m, 1H), 4.52 (m, 1H), 3.82 (dd, J=10.7, 7.2 Hz, 1H), 3.68 (dd, J=10.8, 6.5 Hz, 1H), 2.64 (m, 1H), 2.32 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H).