Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[CH:53][C:54]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[CH:53][C:54]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3[nH]ccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[C:5](C(=O)C)=[CH:4][CH:3]=1.C(C1C=CC2O[C:29]([C:31]([O:33]CC)=[O:32])=C(C)C=2C=1O)(=O)C>>[CH2:14]([O:13][C:11]([C:9]1[O:10][C:6]2[C:5]([O:33][C:31](=[O:32])[CH3:29])=[CH:4][CH:3]=[C:2]([OH:1])[C:7]=2[C:8]=1[CH3:16])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1oc2c(C(C)=O)ccc(O)c2c1C
Reactant: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Product: CCOC(=O)c1oc2c(OC(C)=O)ccc(O)c2c1C

Procedure:
Following the procedure of Example 156 but substituting Ethyl 4-hydroxy-7-acetyl-3-methylbenzofuran-2-carboxylate for the compound of Example 155. There is obtained the intermediate Ethyl-7-acetoxy-4-hydroxy-3-methylbenzofuran-2-carboxylate which is hydrolyzed in an aqueous acetic acid solution of hydrochloric acid (6 hours, 100° C.) to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:47])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH:43][CH2:44][CH2:45][OH:46])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[OH:46][CH2:45][CH2:44][NH:43][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:47])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(NCCO)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc(NCCO)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-{3-[2-(2-hydroxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K50) (250 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (100 mg).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5].Br[CH:12]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:13]=O>CCO.CCOC(C)=O>[Br:10][C:6]1[CH:7]=[CH:8][N:9]2[C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CC(Br)CC(F)(F)F
Reactant: N#Cc1c(Br)ccnc1N
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1c(Br)ccn2c(CC(F)(F)F)cnc12
Temperature: 150 °C
Yield: 48.8 %

Procedure:
A mixture of compounds D8 (2 g, 10.1 mmol) and D4 (2.898 g, 14.14 mmol) in EtOH (10 ml) was subjected to microwave heating at 150° C. for 40 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was diluted with EtOAc and washed with water. The organic layer was separated and washed with water, then with 1M HCl (aqueous solution), dried (MgSO4) and evaporated in vacuo. The crude product thus obtained was triturated with diethylether to yield compound D9 (1.5 g, 48.8%).
Reaction SMILES: O1CCC[CH2:2]1.[Si]([O:13][C:14]([NH:16][CH:17]([CH2:22][CH:23]=[CH2:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15])(C(C)(C)C)(C)C.CI.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:2][O:13][C:14]([NH:16][CH:17]([CH2:22][CH:23]=[CH2:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15]
Reactant: C=CCC(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CI
Product: C=CCC(NC(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (3.0 ml) of the compound prepared in Example 3 (170 mg, 0.59 mmol), were successively added dropwise at 0° C. in a nitrogen atmosphere methyl iodide (0.074 ml, 1.18 mmol) and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.59 ml, 0.59 mmol). The mixture was agitated for 1 hour at 0° C., poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under vacuum. The resulting reaction mixture was subjected to column chromatography and eluted with a 1:4 mixture of ether and hexane to give 93 mg of the titled compound (yield, 84% based on the starting materials used in Example 3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12.CC(C)([O-])C.[K+].[CH3:27][N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]=[C:29]1S(C)(=O)=O.O>CC(N(C)C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:29]4[N:28]([CH3:27])[C:32]5=[N:33][CH:34]=[CH:35][CH:36]=[C:31]5[N:30]=4)=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12
Reactant: Cc1ccnc2c1n1ccnc1n2-c1ccc(O)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a solution of 4-(5-methyl-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (238 mg) in DMA (4 ml) was added potassium tert-butoxide (112 mg) at room temperature. After stirring for 10 min, 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (211 mg) was added, and the obtained mixture was stirred at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (THF) and recrystallized from hexane/THF to give the title compound (229 mg).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[C:4]([SH:7])([CH3:6])[CH3:5].[CH2:11](O)[CH3:12]>>[ClH:1].[CH2:11]([O:9][C:8](=[O:10])[C@H:3]([C:4]([SH:7])([CH3:6])[CH3:5])[NH2:2])[CH3:12]
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)C(C)(C)S
Temperature: -30 °C
Yield: 39 %

Procedure:
Dry hydrogen chloride is bubbled through a suspension of penicillamine (25 g, 0.167 mole) in 300 ml of dry ethanol until all is in solution. The warm solution is then cooled in an ice bath to 0°-5° C. and saturated with dry HCl. The ice bath is removed and the reaction mixture is heated to reflux for 2 hours, then is concentrated in vacuo to a viscous golden oil which is cooled (-30° C.) overnight. After warming to room temperature, the material, now a mixture of white crystalline solid and oil, is triturated with 500 ml Et2O for 30 minutes, then is filtered. An insoluble oil passes through the filter funnel with the Et2O and the residue is washed (3 times, 150 ml portions) further with Et2O. After drying on the funnel under a stream of dry N2, 14.14 g (mp 125°-145° C., 39% yield) of the desired product is obtained as white powder. NMR (CDCl3 ) δ8.85 (bs, 3, --NH3Cl), 4.34 (q, 2, J=7 Hz, OCH2 --C), 4.6-4.15 (m, 1, NCHCO2); 3.83 (s, 1, --SH), 1.70 (s, 3, C--CH3), 1.59 (s, 3, C--CH3), 1.35 (t, 3, J=7 Hz, OCH2CH3); IR (KBr): 1725 cm-1 (s) (C=O).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=O)[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1.[CH3:26][NH:27][NH2:28].O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[N:28][NH:27][CH3:26])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(C=O)oc23)c1=O
Reactant: CNN
Solvent: C1CCOC1
Solvent: O
Product: CNN=Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
0.4 g (1.0 mmol) of 3-(4-chloro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 5 ml of tetrahydrofuran, and 0.1 g (21.7 mmol) of monomethylhydrazine was added thereto under cooling with ice, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.2 g (yield: 47.6%) of the desired product as a pale yellow glassy substance. Refractive index: unmeasurable, 1H-NMR (solvent, CDCl3): 2.90(3H,s), 3.52(3H,s), 6.18(1H,bs), 6.40(1H,s), 6.85(1H,s), 7.05 (1H,d), 7.25(1H,s), 7.29(1H,d) ppm
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:31][CH2:32][C:33](Cl)=[O:34])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:32](=[O:31])[CH2:33][OH:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Product: C[C@H](NC(=O)CO)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 7 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 149 mg, 0.41 mmol) and 2-chloro-2-oxoethyl acetate (49 μL, 0.45 mmol). Yield 125 mg (72%).
Reaction SMILES: [NH2:1]N1C2C=NC=CC=2C2C1=CC(Cl)=CC=2.N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C1COCC1>[C:23](=[O:24])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:1]
Reactant: Nn1c2cnccc2c2ccc(Cl)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 224 %

Procedure:
A cold (3° C. to 5° C.) solution of the product of example 15 (30 mg, 0.14 mmol) and pyridine (0.014 ml, 0.17 mmol) in THF (0.7 ml) was treated with phenyl chloroformate (0.018 ml, 0.145 mmol). After stirring at RT for 2 h, the reaction was partitioned in ethyl acetate and buffer (pH 7.2). The organic layer was dried (brine, Na2SO4) and concentrated to give 43 mg of phenyl carbamate.
Reaction SMILES: CCO.C1(C)C(S([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:32])[C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(=O)C(F)(F)F)=[CH:21][CH:20]=2)(=O)=O)=CC=CC=1.[OH-].[K+]>CCOC(C)=O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:14]2[NH:13][CH:17]=[CH:16][CH:15]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)n1cccc1C(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a stirred EtOH (4 mL) solution containing N-toluenesulfonyl-2-(4-(trifluoroacetylamino)benzoyl)pyrrole (0.500 g, 1.15 mmol), was added 40% KOH solution (2 mL) and the mixture was heated at reflux until thin layer chromatography (TLC) analysis showed complete conversion of the starting material. The resulting solution was cooled to room temperature and diluted with EtOAc (20 mL), and the mixture was evaporated to dryness. The crude product was purified by column chromatography (SiO2, EtOAc:Hexanes) to afford the purified product 2-(4-aminobenzoyl)pyrrole (196 mg, 94% yield). 1H NMR (400 MHz, CD2Cl2, 25° C.) δ4.19 (bs, 2H), 6.33 (m, 1H), 6.72 (d, 2H), 6.88 (m, 1H), 7.10 (m, 1H), 7.82 (d, 2H), 9.90 (bs, 1H); 13C NMR (100 MHz, CD2Cl2, 25° C.) δ 110.9, 114.2, 118.0, 124.5, 128.5, 131.8, 131.9, 151.3, 183.5; HRMS (EI): m/z 186.0793 (100) {M}+.
Reaction SMILES: COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O.[C:30]1([N:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:43][C:44]([C:46]1[CH:51]=[C:50]([Br:52])[CH:49]=[CH:48][C:47]=1O)=[O:45]>>[C:30]1([N:36]2[CH2:37][CH2:38][C:39]3([CH2:43][C:44](=[O:45])[C:46]4[C:47](=[CH:48][CH:49]=[C:50]([Br:52])[CH:51]=4)[O:42]3)[CH2:40][CH2:41]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCN(c2ccccc2)CC1
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: O=C1CC2(CCN(c3ccccc3)CC2)Oc2ccc(Br)cc21

Procedure:
1′-Phenyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one was synthesized according to the procedure for preparation of Intermediate 1, Step A, using 1-phenyl-piperidin-4-one (607 mg, 3.47 mmol) and 2-hydroxy-5-bromoacetophenone (746 mg, 3.47 mmol), giving 650 mg as a white solid.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=2[C:6]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[N+:22]([O-:27])([N+]([O-])=O)=[O:23]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[O:3][C:2]([N+:22]([O-:27])=[O:23])=[C:6]([C:7]3[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:17]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1cccc(-c2c([N+](=O)[O-])oc3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-bromo-5-chloro-3-benzofuranyl)phenylacetic acid in chloroform with 1.5 equivalents of cyclonexene is treated with 1.5 equivalents of dinitrogen tetroxide and stirred for about 20 hours at room temperature. The mixture is washed with water, extracted with saturated sodium bicarbonate solution, then the aqueous extracts are acidified. The mixture is extracted with dichloromethane, which is dried and concentrated. The residue is recrystallized from a mixture of benzene and hexane to provide 3-(5-chloro-2-nitro-3-benzofuranyl)phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:5]2.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(5-chloro-1H-indole-2-yl)-2-methylpropan-1-one (1 mmol) in 15 mL of DMF, was added KOH (2 mmol) at 0° C. The mixture was stirred for 30 min., followed by adding benzyl bromide (2 mmol) slowly. The mixture was warmed up to room temperature and stirred for additional 1 h. The solution was poured into water, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (10% EtOAc:hexane) to yield 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(Cl)(Cl)Cl>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[CH:6]=[C:5]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 51 %

Procedure:
A solution of N-(4-chloro-2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide (16.2 g) in acetic acid (200 ml) was dropwise added to a suspension of iron powder (14 g) in a 5% aqueous acetic acid (30 ml) at 90°-100° C. and refluxed for 1 hour. After being allowed to cool, chloroform was added to the resultant mixture, followed by filtration. The organic layer was separated from the filtrate, washed with a saturated sodium hydrogen carbonate solution, dried and concentrated. The residue was recrystallized from a mixture of ether and petroluem ether to give 7.5 g of N-(3-amino-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 144.5°-146.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[H+].[B-](F)(F)(F)F.CCOCC.[Br:21]N1C(=O)CCC1=O>CC#N>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([Br:21])=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cooled (−20° C.) solution of 2-cyanophenol (30 g, 252 mmole) in dried MeCN (400 mL) was added HBF4.Et2O (45 g, 277.1 mmole), and N-bromosuccinimide (53.8 g, 302.3 mmole). After addition was completed, the mixture was warmed to RT, and stirred in 4 h. The mixture was cooled and quenched by 50% aqueous NaHSO3. The mixture was concentrated to removed excess of MeCN. The off-white solid thus obtained was filtered and dried by air (42.4 g, 85%). 1H-NMR (300 MHz, DMSO-d6): δ6.99 (d, J=8.9 Hz, 1H), 7.67 (dd, J=2.5, 8.9 Hz,1H), 7.88 (d, J=2.5 Hz,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25]#[N:26])[C:9]2=[O:27])=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25](=[N:29][OH:30])[NH2:26])[C:9]2=[O:27])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O)=NO

Procedure:
A mixture of (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)-phenyl)imidazolidin-1-yl)propanenitrile (97 mg, 0.25 mmol), hydroxylamine hydrogen chloride (85.5 mg, 1.23 mmol), K2CO3 (187 mg, 1.35 mmol) and anhydrous ethanol (4 mL) are refluxed for 2 days. The solvent is removed under vacuum. The residue is taken into ethyl acetate, washed with sat. NaHCO3 and brine. The organic phase is dried by Mg2SO4. The solvent is removed under vacuum to afford crude (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N′-hydroxy-propanimidamide which is used directly in the next step without further purification. HPLC-MS calculated for C19H19ClF3N4O2 (M+H+) 427.1, found 427.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:33]([N:35](CC)[CH2:36][CH3:37])[CH3:34].N1CCCC1>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:35]3[CH2:36][CH2:37][CH2:34][CH2:33]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CC
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Solvent: C1CCNC1
Solvent: CC#N
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
To a solution of 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(3,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (3.334 g, 7.31 mmol) in anhydrous acetonitrile (4 mL) was added triethylamine (3.06 mL, 21.94 mmol) and pyrrolidine (1.831 mL, 21.94 mmol). The solution was stirred at 70° C. for 18 hours. A further equivalent of pyrrolidine (0.61 mL, 7.31 mmol) and triethylamine (1.019 mL, 7.31 mmol) were added to the reaction mixture. The solution was stirred at 70° C. for a further 3 hours. The cooled reaction mixture was evaporated in-vacuo and the residue partitioned between ethyl acetate and water/brine (1:1). The organic phase was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a sticky brown gum (4.226 g). The gum was dissolved in the minimum volume of dichloromethane, loaded onto a 340 g silica pre-conditioned cartridge and purified by chromatography using dichloromethane over 1 column volume followed by 0-30% methanol (+1% triethylamine) in dichloromethane gradient over 14 column volumes followed by 30% methanol (+1% triethylamine) in dichloromethane over 3 column volumes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a sticky brown gum (1.838 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:10][C:2]1=2.[S:15]1[C:19]([NH2:20])=[N:18][CH:17]=[N:16]1.C1COCC1.[OH-].[Na+]>Cl>[S:15]1[C:19]([NH:20][S:11]([C:9]2[CH:8]=[CH:7][C:3]3[NH:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)(=[O:13])=[O:12])=[N:18][CH:17]=[N:16]1
Reactant: Nc1ncns1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A vial was charged with 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (from HangZhou Trylead Chemical, Hangzhou, China) (74.42 mg, 0.318 mmol), 1,2,4-thiadiazol-5-amine (70.9 mg, 0.701 mmol), and THF (1991 μL) to give a cloudy solution. The vial was cooled in an ice-bath for 5 min, then sodium hydroxide (6N aq.) (117 μL, 0.701 mmol) was added dropwise. After 45 min, the mixture was allowed to warm to room temperature with the bath. The mixture was diluted with 1N aq. HCl and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (4% MeOH/DCM). Several mixed fractions at the tail end of the elution were discarded, and the remainder that contained product were combined and concentrated to give N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (33.19 mg, 0.111 mmol) as a white foam. m/z (ESI) 299.2 (M+H)+.