Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Tl+3].[C:23]([O:26][CH2:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:25])[CH3:24].[I:36]I.O>FC(F)(F)C(O)=O.C(OCC)C>[C:23]([O:26][CH2:27][C:28]1[C:29]([F:35])=[CH:30][CH:31]=[C:32]([I:36])[C:33]=1[F:34])(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(F)cccc1F
Reactant: II
Agent: O=C([O-])C(F)(F)F
Agent: [Tl+3]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCc1c(F)ccc(I)c1F
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Thallium tris(trifluoroacetate) (24.5 g, 0.045 mole) was added to a stirred solution of 16.8 g (0.090 mole) of (2,6-difluorophenyl)methyl acetate in 60 ml of trifluoroacetic acid. The reaction mixture was heated at 40°-50° C. for 15 minutes then 12.7 g (0.05 mole) of iodine was added. Upon complete addition the reaction mixture was heated under reflux for an additional 2 hours. The solvent was removed under reduced pressure and replaced with an equal volume of methylene chloride. The methylene chloride was removed under reduced pressure to give an oily residue. The residue was poured onto ice, using water and diethyl ether to rinse. The mixture was stirred for 30 minutes as 10 g of sodium metabisulfite and then 40 ml of a 5% aqueous solution of sodium hydroxide were added. The aqueous phase was separated and the organic phase was washed with two portions of water, one portion of a 5% aqueous solution of sodium thiosulfate, two portions of water, and finally one portion of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was distilled under reduced pressure to give 10.5 g of (2,6-difluoro-3-iodophenyl)methyl acetate, b.p. 70°-80° C./2.2 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[C:12]([Si:15]([CH3:17])([CH3:16])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ncc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
In a round-bottomed flask, 5-hydroxy-1H-indazole (700 mg, 5.22 mmol) was dissolved in DMF (15 ml) and TBDMS-Cl (865 mg, 5.74 mmol) and imidazole (426 mg, 6.26 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 1.21 g (93%) of 5-(tert-butyl-dimethyl-silanyloxy)-1H-indazole as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(Cl)(Cl)Cl.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C1COCC1>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[Br:24][C:22]1[CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH2:7])=[NH:9])[S:11][C:12]=2[S:26][CH3:27])(=[O:17])=[O:16])[CH:19]=[N:20][C:21]=1[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: NCc1ccccn1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cnc(NCc2ccccn2)c(Br)c1

Procedure:
The reaction was conducted following the procedure for Example 164: step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), (example 164: step b), 2-aminomethylpyridine (0.014 g, 0.133 mmol), THF [3 mL], followed by chloroform/TFA (1:1) to yield the title compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 499.1, 501.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([N:8]=[C:10]=[S:11])=[N:6][CH:7]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1cc(N)ncc1Cl
Solvent: ClCCl
Product: Cc1cc(N=C=S)ncc1Cl
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To 5-chloro-4-methylpyridin-2-amine (0.41 g, 2.88 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.70 g, 3.0 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature. The crude mixture was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 5-chloro-2-isothiocyanato-4-methylpyridine (0.45 g, 2.44 mmol, 85% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.45 (s, 1 H), 7.47 (s, 1 H), 2.37 (s, 3 H). LC/MS RT=2.79; [M+H]+=184.9.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=2)[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(OC(=O)c4ccc(F)cc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Dissolve the compound of Example 3 (111 mg, 0.21 mmol) in dichloromethane (2 mL). Add 4-fluorobenzoyl chloride (30 μL, 0.25 mmol) dropwise. After stirring for 10 minutes, pour the reaction-mixture into saturated aqueous sodium bicarbonate (10 mL) and extract with dichloromethane (10 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 3%) to give 99 mg of the title compound (73%): mass spectrum (ion spray): m/z=640.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([OH:21])([CH3:20])[CH3:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].S(=O)(=O)(O)O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([O:21][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])([CH3:20])[CH3:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C12CC3CC(C1)CC(C(C)(C)O)(C3)C2
Reactant: C=C(C)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)OC(C)(C)C12CC3CC(CC(C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
In a flask equipped with a stirrer, a thermometer, a dropping funnel, and a Dimroth condenser, 50 g of 3-(1-hydroxy-1-methylethyl)adamantane-1-carboxylic acid t-butyl ester, 200 mL of dichloroethane, and 80 g of pyridine were put, and 71.7 g of methacrylic acid chloride was dropped thereto at 60° C. over 2 hours. After the dropping was completed, the resultant substance was stirred at 60° C. for another 8 hours. Then, the resultant substance was neutralized with 320 g of 10% aqueous solution of sulfuric acid while the flask was ice-cooled. The reaction solution was separated into an organic layer and a water layer. The organic layer was washed twice with 500 mL of ion exchanged water, and then was concentrated. The obtained raw product was purified by silica gel column chromatography. As a result, 25 g of 3-(1-methacryloyloxy-1-methylethyl)adamantane-1-carboxylic acid t-butyl ester was obtained as a white solid. White solid 2, which was obtained, was identified with 1H-NMR, 13C-NMR and IR (see FIGS. 2, 3 and 4).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6](=C)[C:7]([NH2:9])=[O:8].[CH3:11]O>>[CH3:11][NH:9][C:7](=[O:8])[CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2]
Reactant: CO
Reactant: C=C(C)C(N)=O
Reactant: CC(C)N
Product: CNC(=O)CCNC(C)C
Temperature: 140 °C
Yield: 94 %

Procedure:
Isopropylamine (Aldrich; 1.5 ml, 17.62 mmol) and methyl acrylamide (ABCR; 1.0 g, 11.75 mmol) were combined in methanol (10 ml). The mixture was heated in a microwave at 140° C. for 30 min. The reaction was repeated and the combined reaction mixtures were concentrated to remove excess amine. The residue was re-dissolved in methanol and absorbed onto an SCX column (50 g), washed with methanol and eluted with ammonia/methanol. Concentration of the product containing fractions gave the title compound as a colourless oil (3.2 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[N:16]([CH3:15])[N:17]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: CN1N=C(c2ccc(Cl)cc2)CCC1=O

Procedure:
To a 250 ml flask equipped with magnetic stirrer and reflux condenser was charged 10 g of 3-(4-chlorobenzoyl)-propionic acid, 250 ml. of absolute ethanol, and 2.5 ml of methyl hydrazine. The reaction was refluxed for 3 hours and cooled to yield a solid which was collected by vacuum filtration, washed with 50 ml of hexane, and air dried. Isolated 9.5 g of product as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[Cl:21])=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:18]1[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=1)=[N:13][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:20]=2
Reactant: Brc1ccccn1
Reactant: C#CCCn1cc2c(Cl)cccc2n1
Product: Clc1cccc2nn(CCC#Cc3ccccn3)cc12
Yield: 17916.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.27 mmol) and 2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol). Reaction time: 8 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 12 mg (43 mmol, 17%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: F[CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[C:11]([O:38][CH3:39])[CH:10]=2)[CH2:5]1.FC(F)(F)C(O)=[O:43]>O1CCOCC1>[C:3]([N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:19]([C:34]([F:36])([F:35])[F:37])=[CH:18][N:17]=3)=[C:11]([O:38][CH3:39])[CH:10]=2)[CH2:5]1)(=[O:43])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(CCF)C4)cc3OC)ncc2C(F)(F)F)c1
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(C(C)=O)C4)cc3OC)ncc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
As shown in Scheme 2, a mixture of intermediate 1 of Scheme 2 (16 mg) and intermediate 3 of Scheme 1 (1-(3-(4-amino-3-methoxyphenylamino)azetidin-1-yl)ethanone, 20 mg) in dioxane (1.0 mL) with catalytic trifluoroacetic acid was stirred overnight at 50° C. The crude was concentrated under reduced pressure and purified using HPLC (TFA modifier) to give the title compound (12 mg) as a TFA salt. 1H-NMR (DMSO-d6, 400 MHz) δ 10.6 (s, 1H), 10.15 (s, 1H), 9.45 (s, 1H), 8.62 (br, 1H), 6.96-7.85 (m, 4H), 6.55 (dd, J=2, 10 Hz, 1H), 6.23 (d, J=10 Hz, 1H), 5.74 (d, J=10 Hz, 1H), 3.15-3.85 (m, 6H), 1.77 (s, 3H); calculated mass for C26H26F3N7O3: 541.2. found: 542.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](=[O:52])[NH:19][CH:20]([C:45]2[CH:50]=[CH:49][C:48](Cl)=CC=2)[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[C:38]4[CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH2:35][CH2:34][C:33]=4[CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[C:53](O)([C:55](F)(F)F)=O.[CH2:60]([Cl:62])Cl>>[Cl:62][C:60]1[CH:48]=[CH:49][C:50]([CH2:45][CH:20]([NH:19][C:18]([CH:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)=[O:52])[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[C:38]4[CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH2:35][CH2:34][C:33]=4[CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:55][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NC(C(=O)N1CCC(c2cccc3c2CC(N2CCOCC2)CC3)CC1)c1ccc(Cl)cc1
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Product: O=C(NC(Cc1ccc(Cl)cc1)C(=O)N1CCC(c2cccc3c2CC(N2CCOCC2)CC3)CC1)C1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To compound prepared in Example 19 (0.42 g, 0.567 mmol), in DCM (3 mL), is added TFA (3 mL) and the mixture is stirred at room temperature for about 45 minutes. After concentrating to dryness, the resulting residue is triturated with Et2O, and the resulting solid is collected by filtration and dried to afford about 0.47 g of the final product (94%). EIS-MS 641.2 [M+1]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12](=[O:16])[CH:13](Br)[CH3:14].C([O-])([O-])=O.[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:13]([CH3:14])[C:12]([O:11][CH3:10])=[O:16]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)C(C)Oc1ccc(Cl)cc1Br

Procedure:
A mixture of 2-bromo-4-chlorophenol (250 mg; 1.21 mmol) and methyl-2-bromopropionate (VWR; 135 μL, 1.21 mmol) in DME (5 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and refluxed for 18 hours. The reaction mixture was filtered, the filtrate was concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a yellow liquid (306 mg; 87%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH3:22]OC(=O)OC.CN(C)C=O>O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH3:22])[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)OC
Reactant: O=C1NCc2cccnc2N1c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 76.3 %

Procedure:
A mixture of 0.5 g 1-(m-trifluoromethylphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 0.8 g of dimethylcarbonate and 10 ml of dimethylformamide was reacted at 160° - 170° C in sealed-tube for 20 hours. After the reaction was finished, the solvent was distilled off from the mixture to leave a residue, to which was added water. This residue was extracted with ether and then dehydrated. The ether solution was applied on a column of alumina, and then eluted with ether. The ether was evaporated from the eluate and left to give 0.4 g of 1-(m-trifluoromethylphenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 122° - 124° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[O:26][C:22]=2[C:21](F)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:19]=1[CH3:44])#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 5 h
Yield: 28.9 %

Procedure:
(3S)-3-(dimethylamino)pyrrolidine (161 μl, 1.27 mmol) and triethylamine (177 μl, 1.27 mmol) were added to a dimethyl sulfoxide (9 ml) solution of tert-butyl N-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-β-alaninate (I-278) (335 mg, 0.847 mmol), followed by stirring in an oil bath at 150° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1, v/v) to obtain the entitled compound (120 mg, 29%) as a brown oily substance.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(=[O:15])[CH2:14][CH2:13][CH:12]=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+]>O>[C:1]1([CH:12]2[CH2:13][CH2:14][C:10](=[O:15])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCC(c2ccccc2)C1
Temperature: 80 °C

Procedure:
A mixture of phenylboronic acid (1.63 g, 13.4 mmol), cyclopent-2-enone (1.0 g, 10.4 mmol), and Na2CO3 (2.2 g, 20.8 mmol) was purged with nitrogen for 15 min followed by the addition of [Rh(cod)Cl]2 (100 mg, 0.21 mmol) and water (30 mL). The resulting suspension was heated to 80° C. for 20 min. The mixture was extracted with CH2Cl2, washed with brine, dried over MgSO4 and chromatographed on silica gel using 3:1 hexanes:ethylacetate to afford the title compound as a colorless oil. MS m/z: 161 (M+1).
Reaction SMILES: [NH4+].[Cl-].[C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[C:18]([C:20]2[C:28]3[C:23](=[N:24][C:25](C#N)=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C@H:13]([CH3:32])[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:33]=[N+:34]=[N-:35].[Na+].[CH3:37][N:38](C=O)C>>[C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[C:18]([C:20]2[C:28]3[C:23](=[N:24][C:25]([N:33]4[CH:37]=[N:38][N:35]=[N:34]4)=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C@H:13]([CH3:32])[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2nc(C#N)ccc12
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2nc(-n3cnnn3)ccc12

Procedure:
An excess of NH4Cl (27 mg) was added into a solution of 1-(benzoyl)-3-(R)-methyl-4-[(6-cyano-7-azaindol-3-yl)-oxoacetyl]piperazine (20 mg) and NaN3 (16 mg) in DMF. The reaction was heated to reflux for 12 h. After cooling down, the mixture was concentrated under reduced pressure and the residue was purified using Shimadzu automated preparative HPLC System to give 1-benzoyl-3-(R)-methyl-4-[(6-(tetrazol-1-yl)-7-azaindol-3-yl)-oxoacetyl]piperazine (6.3 mg). MS m/z: (M+H)+ Calc'd for C22H21N8O3: 445.17; Found 3445.16. HPLC retention time: 1.42 minutes (column B); Column B: PHX-LUNA C18 4.6×30 mm.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1)(=[O:36])=[O:35]
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Yield: 97.7 %

Procedure:
Triethylamine (0.88 g, 8.70 mmol) was added to a solution of ethyl 4-(2(4-(2-hydroxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (1.50 g, 4.37 mmol) in methylene chloride (40 ml). The mixture was stirred under ice-cooling, and methanesulfonyl chloride (0.60 g, 5.24 mmol) was added dropwise to the mixture. The resulting mixture was stirred under ice-cooling for 10 minutes after the addition. Then, water (40 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=1/1) to give the desired ethyl 4-(2-(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (1.80 g, 98%).
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]([C:20]#[N:21])=[CH:12][N:11]=2)C=CC=CC=1.C(C1C=CC(NC([N:34]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]3[CH:41]=[CH:42][C:43]([CH:45]([O:48]C)OC)=[N:44][C:35]2=3)=O)=NC=1)#N.[CH3:50][N:51]([CH:53]=[O:54])[CH3:52]>>[C:20]([C:13]1[C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[CH:15][C:10]([NH:9][C:8]([N:34]2[C:35]3[C:36](=[CH:41][C:42]([CH2:50][N:51]4[CH2:52][CH2:52][N:51]([CH3:53])[CH2:50][C:53]4=[O:54])=[C:43]([CH:45]=[O:48])[N:44]=3)[CH2:37][CH2:38][C@@H:40]2[CH3:39])=[O:22])=[N:11][CH:12]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2
Reactant: CC(C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Product: CC(C)Oc1cc(NC(=O)N2c3nc(C=O)c(CN4CCN(C)CC4=O)cc3CC[C@@H]2C)ncc1C#N

Procedure:
From intermediates 96 and 268, coupled and deprotected in an analogous manner to intermediate 236, but using DMF instead of THF, and Example 201. The title compound was obtained as a light brown solid.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1)=[O:17]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:15]2[O:3][C:4]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=3[CH:6]=2)=[O:17])=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26]
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1cccc(C=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc2cc(C(=O)c3ccc(Cl)c([N+](=O)[O-])c3)oc12
Reaction time: 8 h

Procedure:
2 g KOH are dissolved in 50 ml methanol, a solution of 5.4 g 2-hydroxy-3-methoxybenzaldehyde is added and subsequently a suspension of 10 g 2-bromo-4'-chloro-3'-nitroacetophenone in 75 ml methanol. The batch is refluxed for 6 hours, agitation is continued overnight at room temperature, and the crystals are suction-filtered. M.p. 136° C. (from ethyl acetate).