Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])[C:15](=[O:33])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:41][CH2:42][CH2:43][CH2:44][O:45][C:46]1[CH:51]=[CH:50][N:49]([CH:52]2[CH:57]([OH:58])[CH2:56][CH2:55][N:54]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53]2)[C:48](=[O:66])[CH:47]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Br[CH2:68][C:69]1[CH:78]=[CH:77][C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH:70]=1>>[CH2:34]([O:41][CH2:42][CH2:43][CH2:44][O:45][C:46]1[CH:51]=[CH:50][N:49]([CH:52]2[CH:57]([O:58][CH2:68][C:69]3[CH:78]=[CH:77][C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=3)[CH2:56][CH2:55][N:54]([C:59]([O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[O:60])[CH2:53]2)[C:48](=[O:66])[CH:47]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH:20]2[O:32][CH2:68][C:69]2[CH:78]=[CH:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[CH:70]=2)[C:15](=[O:33])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCCCOCc3ccccc3)cc2=O)C(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(n2ccc(OCCCOCc3ccccc3)cc2=O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc3ccccc3c2)C(n2ccc(OCCCOCc3ccccc3)cc2=O)C1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(OCCCOCc3ccccc3)cc2=O)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 145 (h), from a mixture of tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-hydroxy-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,4']bipyridine-1'-carboxylate and tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-4'-hydroxy-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,3']bipyridine-1'-carboxylate by means of alkylation with 2-bromomethyl-naphthalene and after chromatographic separation of the two isomers on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent there was obtained tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-4'-(naphthalen-2-ylmethoxy)-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,3']bipyridine-1'-carboxylate, (Rf : 0.64, SiO2 ; methylene chloride:ethyl acetate=1:4 v/v), and tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,4']bipyridine-1'-carboxylate, MS: 599 (M+H)+, (Rf : 0.44, SiO2 ; methylene chloride:ethyl acetate=1:4 v/v), each as a yellowish oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[F:16][C:17]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:18]=1[C:19]([Cl:21])=[O:20]>>[ClH:21].[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH:15][C:19](=[O:20])[C:18]3[C:22]([F:27])=[CH:23][C:24]([F:26])=[CH:25][C:17]=3[F:16])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Product: CN1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Product: Cl
Yield: 87.9 %

Procedure:
Using a method similar to example 154, using 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 200 mg, 0.965 mmol) and 2,4,6-trifluorobenzoyl chloride (150 μL, 1.16 mmol) yields of the title compound (341 mg, 88%). Mass spectrum (ion spray): m/z 365.8 (M+1); Analysis calculated for C18H19N3O2ClF3. Theory: C, 53.81; H, 4.76; N, 10.46. Found: C, 53.74; H, 5.03; N, 10.43. mp=264-6° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14]>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCN(CC2CC2)CC1
Agent: Cl
Product: ON=C1CCN(CC2CC2)CC1

Procedure:
1-(Cyclopropylmethyl)-4-piperidone oxime is prepared from 1-(cyclopropylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[C:49]([C:57]([OH:59])=O)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[O:56]=[C:49]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:57]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:59]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C(=O)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with benzoylformic acid, mp 106°-109° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:15]
Reactant: Nc1nccs1
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(C(=O)Nc1nccs1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Referring to Scheme 3, a mixture of 2-(1,3-dioxoisoindolin-2-yl)-4-methylpentanoic acid (78 mg, 0.3 mmol), 2-aminothiazole (30 mg, 0.3 mmol), HBTU (114 mg, 0.3 mmol) and 0.1 mL of Et3N in DMF (2 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, MeOH-d4) δ: 7.83-7.86 (m, 2H), 7.89-7.92 (m, 2H), 7.41 (d, J=3.2 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 5.15 (dd, J=4.8, 11.6 Hz, 2H), 2.35-2.45 (m, 1H), 1.96-2.05 (m, 1H), 1.51 (m, 1H), 0.99 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H). [M+H] calc'd for C17H17N3O3S, 344; found, 344.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:21](=[O:22])[O:23][CH:24]([CH3:26])[CH3:25])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)OC(C)C)ncc2c1
Yield: 74 %

Procedure:
A solution 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (52.0 mg, 206 μmol) in pyridine (1.0 mL) was treated dropwise with a solution isopropyl chloroformate (210 μl, 1.0M, 210 μmol) at ambient temperature for 30 mins, and the mixture concentrated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a residue that was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white powder (51.6 mg, 74%). 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 9.13 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.5, 1.6 Hz, 1H), 7.37 (dd, J=7, 6 Hz, 1H), 7.22-7.13 (m, 2H), 4.96 (septet, J=6.2 Hz, 1H), 2.25 (s, 3H), 1.29 (d, J=6.3 Hz, 6H). LCMS (Method E): RT=6.067 min, M+H+=339.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1I.[I:12]C1C=C(C=C([N+]([O-])=O)C=1)N>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[C:6]([I:12])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1I
Reactant: Nc1cc(I)cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
1-Fluoro-3-nitroiodobenzene To a 25 mL round-bottom flask equivuipped with a magnetic stir bar 3-iodo-5-nitroaniline (543.3 mg, 2.06 mmol) and methylene chloride (10 mL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 min. The solution was cooled to 0° C. in an ice bath. At that point approximately 500 mg nitrosonium tetrafluoroborate was added in one portion making a cloudy precipitate. The reaction was allowed to continue stirring for 2 hours. The mixture was kept under nitrogen as 10 mL dry, deoxygenated ortho-dichlorobenzene was added. A distillation apparatus was fitted to the reaction flask. The flask was placed in an oil bath and was heated until the material had completely distilled over. The crude product was isolated by washing the residue through a short column (74 mL silica, hexane). Purification by silica gel chromatography (74 mL silica, hexane) afforded 279.4 mg (50%) of 5-fluoro-3-nitroiodobenzene. Data for 5-fluoro-3-nitroiodobenzene: 1H NMR (400 MHz, acetone-d6) 8.36 (s, 1 H), 8.00 (m, 2 H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1.Cl>CCCCCC.CCOCC.CCOCC.CCCCCC>[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[C:10](=[N+:30]=[N-:31])[C:9]=2[CH:8]=1
Reactant: Fc1ccc2c(c1)Cc1cc(F)ccc1-2
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [N-]=[N+]=C1c2cc(F)ccc2-c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
Under nitrogen, n-butyllithium (20 mL of a 2.5M solution in hexane, 1 eq) was added dropwise to a stirred, -20 ° C. solution of commercially available (Alfred Bader Library of Rare Chemicals) 2,7-difluorofluorene (24) (10 g, 49.5 mmoL) [which may also be prepared according to U.S. Pat. No. 4,436,745] in 250 mL of anhydrous ether. After 10 min., this mixture was transferred via a cannula using nitrogen pressure into a 0° C. solution of p-toluenesulfonylazide [prepared by the method described in Doering, et al. J. Am. Chem. Soc. (1953) 75, 5955] in 200 mL of anhydrous ether over 20 min. The reaction was allowed to warm to room temperature over 1.5 h and was then acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine (3×100 mL), dried (MgSO4), and concentrated to provide 10 g of crude material which was leached with ether/hexane to provide 4 g (37%) of product (25): mp 148°-150 ° C.; IR (KBr) 2070, 1600, 1575, 845 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.77 (ddd, 2H, J=0.5, 5.0, 8.7Hz), 7.14 (ddd, 2H, J=0.5, 2.5, 8.5Hz), 7.0 (ddd, 2H, J=2.3, 8.5, 9.3Hz); MS m/z 228 (M+), 200 (base peak). Anal. Calcd. for C13H6N2F2 : C, 68.42;H, 2.65; N, 12.28. Found: C, 68.25;H, 2.78; N, 12.50.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]([C:9](O)([CH3:11])[CH3:10])[CH:6]=[CH:5][N:4]=1.S(=O)(=O)(O)[OH:16].[C:20](#[N:22])[CH3:21]>>[CH3:10][C:9]([NH:22][C:20](=[O:16])[CH3:21])([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[N:8]=1)[CH3:11]
Reactant: O=S(=O)(O)O
Reactant: CC#N
Reactant: CC(C)(O)c1ccnc(C(F)(F)F)n1
Product: CC(=O)NC(C)(C)c1ccnc(C(F)(F)F)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Heat a solution of acetonitrile (300 mL) and 2-(2-trifluoromethyl-pyrimidin-4-yl)-propan-2-ol (16.5 g, 80 mmol) to 90° C. In a separate reaction vessel, cool acetonitrile (70 mL) to 0° C. and add sulfuric acid (19.2 mL, 360 mmol) at such a rate that the temperature does not exceed 10° C. Add the cooled sulfuric acid solution to the heated solution of 2-(2-trifluoromethyl-pyrimidin-4-yl)-propan-2-ol and acetonitrile and stir at 90° C. for 60 minutes. Cool to room temperature, concentrate to about ⅓ original volume, and add aqueous 5N NaOH (150 mL). Partition between ethyl acetate and brine then extract the aqueous layer with ethyl acetate (3×). Concentrate under reduced pressure the combined organic layers to yield N-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethyl]-acetamide (15.4 g, 78%) as a yellow solid. MS (m/z): 248.0 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[C:19]([O:21]CC)=O)#[N:2].[BH4-].[Na+]>C1COCC1.CO.CCOC(C)=O>[O:21]=[C:19]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3][CH2:1][NH:2]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CCC#N)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 0 °C
Yield: 84.2 %

Procedure:
To a suspension of diethyl 1-(2-cyanoethyl)-1H-indole-2,6-dicarboxylate (1.5 g, 4.8 mmol) in THF (12 mL) and methanol (16 mL) is added CoCl2 (1.3 g, 9.6 mmol). The bright blue suspension/solution is cooled to 0° C., and NaBH4 (1.8 g, 48.0 mmol) is carefully added in small portions. As each portion is added H2 is formed violently and the suspension becomes black. After the addition of NaBH4 is complete, the mixture is warmed up room temperature for 60 min and is then heated at reflux for 16 h. The mixture is cooled to room temperature and is diluted with EtOAc. The mixture is filtered through Celite, and the gummy solids are washed with EtOAc. The combined EtOAc filtrate is washed with 3M HCl, water, NaHCO3, brine, dried (Na2SO4) and concentrated to afford the title crude compound (1.1 g, 85%) which is used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][O:22]C(=O)CC)[C:15]([CH:16]=[C:17]([O:31]CC)[CH2:18][C@@H:19]1[CH3:30])=[CH:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3]>C(OCC)(=O)C.[Pt]=O>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[OH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][OH:22])[C@H:15]([CH2:16][C:17](=[O:31])[CH2:18][C@@H:19]1[CH3:30])[CH2:14][CH2:13]3
Reactant: CCOC1=CC2=CC[C@H]3[C@@H]4CC[C@H](OC(=O)CC)[C@@]4(C)CC[C@@H]3[C@@]2(COC(=O)CC)[C@@H](C)C1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCC(=O)O
Product: C[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-ethoxy-1α-methyl-3,5-androstadien-17β,19-diol dipropionate in ethyl acetate is hydrogenated with platinum oxide at atmospheric pressure. The solution is filtered and the solvent removed under reduced pressure. The residue is taken up in aqueous methanol containing a drop of hydrochloric acid and stirred for 20 minutes at room temperature. The methanol is removed and ether added. The ether extract is washed with water, dried over magnesium sulfate and concentrated. Crystallization of the residue from an acetone-hexane solution yields 17β,19-dihydroxy-1α-methyl-5α-androstan-3-one dipropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH2:28][CH3:29])=[O:15])=[CH:19][CH:20]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(Oc1ccc(CNc2ccc(Cl)cc2)cc1)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Product: Cl

Procedure:
A mixture of 6.27 g of 2-[4-(4-chloroanilinomethyl)-phenoxy]-2-methylpropionic acid, 120 ml of absolute ethanol and 2.2 g of concentrated sulfuric acid is refluxed under heating for 3 hours and 40 minutes. The ethanol is distilled off from the reaction mixture under reduced pressure. The residue is basified with a dilute aqueous solution of sodium bicarbonate, and the resulting solution is extracted three times with ether. The extract is washed with water once, then with a dilute aqueous solution of sodium bicarbonate twice and thereafter with water twice and is subsequently dried over magnesium sulfate. The dried extract is concentrated under reduced pressure, and the resulting oily concentrate is dissolved in ether. Ethanol and hydrochloric acid are added to the solution, and the precipitated crystals are collected by filtration, washed with ether and recrystallized from isopropyl alcohol to give 4.8 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate hydrochloride in the form of colorless flakes, mp 143° to 146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.[NH3:35]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:35])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:29])([F:30])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: N
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Solvent: CO
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(N)=O)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A round bottom flask was mixed with 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoyl chloride (0.037 g, 0.07 mmol) and 2.0 M NH3 in MeOH (5.0 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The resulting solid was crystallized with Et2O, filtered in vacuo and dried under high vacuum to afford a pure solid (0.021 g, 58% yield): MS (ES) m/z 487 (M+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[O:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:32])=[O:33])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 72.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)piperidine-1-carboxylate (intermediate 13) (150 mg, 0.222 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (106 mg, 0.334 mmol) using Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) and sodium carbonate (59 mg, 0.557 mmol) in toluene/ethanol/water (4/1/1 ml) to afford 120 mg (71.8% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=750.4 (M+1).
Reaction SMILES: CO/[N:3]=[CH:4]/[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([F:12])[C:6]=1F.O.[NH2:15]N>C1COCC1>[Br:11][C:9]1[CH:10]=[C:5]2[C:6](=[C:7]([F:12])[CH:8]=1)[NH:15][N:3]=[CH:4]2
Reactant: NN
Reactant: CO/N=C/c1cc(Br)cc(F)c1F
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc2cn[nH]c12
Temperature: 90 °C

Procedure:
A mixture of (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65 g, 78.6 mmol), hydrazine hydrate (80 mL), and dry THF (80 mL), was heated at 90° C. for 84 h. Work-up: the organic solvent was evaporated. The resulting mixture was diluted with EtOAc (400 mL), washed with water (150 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0=20% EtOAc in petroleum ether) to give 5-bromo-7-fluoro-1H-indazole as a white solid (9.3 g). 1H NMR (300 MHz, CDCl3): δ 13.83 (br, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.45 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][N:38]([CH3:40])[CH3:39])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][N:38]([CH3:39])[CH3:40])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)CN(C)C)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)CN(C)C)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-19 (0.165 g) and lithium hydroxide (45 mg) were added to tetrahydrofuran (4 ml) and water (2 ml). The same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 80 mg (51%); mp 175-176° C., MS APC-ve 604 (M−H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH2:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14]>C(O)C>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:15]([CH2:13][CH3:14])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)[C:10]#[C:11][CH3:12]
Reactant: CCNCc1ccccc1
Reactant: CC#CCOc1cc(Cl)ncn1
Solvent: CCO
Product: CC#CCOc1cc(N(CC)Cc2ccccc2)ncn1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To 4 ml of ethanol were added 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.68 g of N-ethyl-N-benzylamine, followed by heating under reflux for 6 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. A saturated aqueous ammonium chloride solution was poured onto the residue, which was extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.42 g of 6-(2-butynyloxy)-4-(N-ethyl-N-benzylamino)pyrimidine (the present compound (129)).