Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-:21].[Na+]>Cl>[CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:21])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CN(C)c1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Agent: Cl
Agent: [Na+]
Product: CN(C)c1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Yield: 52.1 %

Procedure:
A solution of 3-[4-(dimethylamino)phenyl]-1H-indazole-5-carbonitrile (125 mg, 0.476 mmol) in 5.00 mL of concentrated aq. HCl was heated at 47° C. for 1 h, and then added dropwise with stirring to 20 mL of 6.0 N aq. NaOH that was cooled in a water bath. The mixture was extracted with 2×EtOAc, and the combined organics were dried (Na2SO4). Purification by silica gel chromatography using EtOAc as eluent afforded the title compound (69.3 mg, 52.1% yield): 1H NMR (DMSO-d6) δ 13.19 (s, 1H), 8.58 (s, 1H), 8.10 (br s, 1H), 7.9S-7.82 (m, 3H), 7.56 (d, 1H), 7.30 (br s, 1H), 6.84 (d, 2H), 2.98 (s, 6H); ES-MS (m/z) 281 [M+1]+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1([C:18]2[N:19]=[CH:20][NH:21][CH:22]=2)[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[O:8][C:7](=[O:17])[CH2:6]1.C(N(C(C)C)C(C)C)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C>ClCCl.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[O:8][C:7](=[O:17])[CH2:6][C:5]3([CH2:4][CH2:3][CH2:2][N:19]4[CH:20]=[N:21][CH:22]=[C:18]34)[C:14]2=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)OC(=O)CC2(CCCO)c1c[nH]cn1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)OC(=O)CC21CCCn2cncc21
Reaction time: 3 h

Procedure:
A solution of 1.20 mmol of 4-(3-hydroxypropyl)-4-(1H-imidazol-4-yl)-7-methoxychroman-2-one and 1.44 mmol of N-ethyldiisopropylamine in 10 ml of dichloromethane is admixed dropwise at room temperature with 1.20 mmol of methanesulphonyl chloride and the reaction mixture is subsequently stirred for 3 hours. The conversion to the mesylate intermediate is observed by means of HPLC. The reaction mixture is poured into 10 ml of water and subjected to extraction and the aqueous phase is re-extracted with dichloromethane (2×). The combined organic phases are washed with brine, dried over sodium sulphate and evaporated (bath temperature: 30° C.). The residue is taken up in 10 ml of acetonitrile and heated at boiling on an oil bath for about 20 hours. The reaction mixture is left to cool and then evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperidine-1-carboxylate (0.0503 g, 0.130 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0173 g, 0.119 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperidine-1-carboxylate (0.0293 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:20])=O>Cl.C(N(CC)CC)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([Cl:20])=[O:9]
Reactant: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cccnc1Oc1cccc(Cl)c1
Yield: 97.8 %

Procedure:
In the same manner as in Example 1(b) the 22.1 grams of 2-(3-chlorophenoxy) nicotinic acid was combined with 13.0 grams (0.1 mole) thionyl chloride, 0.5 grams triethylamine hydrochloride and 200 milliliters chloroform to produce 23.2 grams (98.3% of theoretical yield) of 2-(3-chlorophenoxy)nicotinoyl chloride, m.p. 72°-74° C.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]1.[N:17]#[N:18].C([O-])(O)=O.[Na+].BrN1C(=O)CCC1=O>CC(C)=O.O.C1COCC1>[N:17]1[CH:5]=[CH:4][CH:3]=[C:2]([C:6]2([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]2)[N:18]=1
Reactant: N#N
Reactant: CC(C)(C)OC(=O)NC1(c2ccco2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2cccnn2)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(furan-2-yl)cyclopropylcarbamate (2.15 g, 9.64 mmol, 1.0 eq) in acetone (86 ml) and water (86 ml) was purged N2 and cooled to −20° C. NaHCO3 (1.62 g, 19.28 mmol, 2.0 eq) and N-bromosuccinimide (2.23 g, 12.52 mmol, 1.3 eq) were added to the mixture at −20° C. which was stirred at the same temperature for 2 hr. To the reaction mixture at −20° C. was added THF (4.3 ml) and the temperature raised to 0° C. over 30 min. Acetone was removed from the reaction mixture by a stream of N2 and to the residue at 0° C. was added isopropanol (86 ml) followed by hydrazine hydrate (12.9 ml). The reaction mixture was stirred at r.t. overnight. Product formation was confirmed by LCMS. After removal of the solvent by vacuum, the residue was diluted with water and extracted with EtOAc. The organic was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent. Yield: 0.8 g (36%). 1H NMR (400 MHz, CDCl3): δ8.95 (d, J=3.6 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.39 (m, 1H), 5.45 (bs, 1H), 1.82 (m, 2H), 1.46 (s, 9H) 1.24 (m, 2H). LCMS: (ES+) m/z=236.2 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:43]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:44])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)C1CCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure D using cyclopentanecarbonyl chloride. The final product was obtained in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([N+:15]([O-])=O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:22][C:23]([C:25]1[CH:48]=[CH:47][C:28]2[N:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:30]([C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([CH:39]=O)[CH:33]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])C.[OH-].[K+].Cl>C(O)C>[NH2:15][C:9]1[CH:10]=[C:11]([C:12]2[CH:13]=[CH:39][C:34]3[C:35](=[CH:36][CH:37]=[C:32]([C:30]4[N:29]([CH:41]5[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]5)[C:28]5[CH:47]=[CH:48][C:25]([C:23]([OH:24])=[O:22])=[CH:26][C:27]=5[N:31]=4)[CH:33]=3)[N:38]=2)[C:6]([C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 12.6 %

Procedure:
1-(4′-Chloro-4-nitro-biphen-2-yl)-ethanone (69 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. for 3 days. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 18 mg product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[NH:7][C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:18]=[C:8]1[NH:7][C:6]2[CH:19]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])[CH:3]=[CH:4][C:5]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH2:9]1
Reactant: C=CC(=O)OC
Reactant: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)NC(=O)CN=C2c1ccccc1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
Title compound 354 (400 mg, 1.28 mmol), methyl acrylate (132 mg, 1.54 mmol), Pd2(dba)3 (16 mg, 0.038 mmol), POT (24 mg, 0.07 mmol) and triethylamine (0.446 mL, 3.2 mmol) were mixed in DMF (15 mL). The mixture was degassed with nitrogen for 5 minutes and the reaction mixture was heated to 100° C. for 2 hours. The DMF was removed and the residue was partitioned between ethyl acetate and water. The 2 layers were split and the aqueous layer was extracted with 2 other portions of ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (50% to 65% ethyl acetate in hexanes) to afford title compound 355 (135 mg, 33%) as a light yellow solid. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.68 (d, J=16.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.24 (d, J=6.4 Hz, 2H), 7.16 (td, J=7.5, 1.0 Hz, 1H), 6.70 (d, J=16.2 Hz, 1H), 4.12 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12](OC)=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O=C1C2C(C(OCC)=O)=CC=CC=2NC(C2C=CC=CN=2)C1C1C=CC=CN=1.O.[NH2:57][NH2:58]>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:4]1[NH:5][C:6]2[C:11]3[C:2](=[N:57][NH:58][C:12](=[O:13])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccn1)C(c1ccccn1)N2
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccccn1)C(c1ccccn1)N2
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccn1)C2c1ccccn1
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of methyl 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (68 mg, 0.19 mmol) in hydrazine monohydrate (7 mL) was heated to reflux for 4 hr. Then the mixture was cooled to room temperature and solvent was removed in vacuum to give crude product. The crude product was purified by pre-HPLC to give 8,9-di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (24 mg, yield 37%) as a light yellow solid. 1H-NMR (400 MHz, DMSO) 5.42-5.43 (d, J=5.2 Hz, 1H), 5.56-5.57 (d, J=5.2 Hz, 1H), 7.30-7.32 (d, J=8.0 Hz, 1H), 7.37-7.39 (d, J=8.0 Hz, 1H), 7.63-7.66 (t, J=6.6 Hz, 1H), 7.68-7.70 (m, 2H), 7.78-7.80 (d, J=7.2 Hz, 1H), 7.87-7.89 (d, J=8.0 Hz, 1H), 8.11-8.16 (m, 2H), 8.66-8.67 (d, J=4.8 Hz, 1H), 8.74-8.76 (d, J=5.6 Hz, 1H); LC-MS (ESI) m/z: 342 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14](=[O:15])[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][C:6]1=[O:16].[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[ClH:1].[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]2[C:14](=[O:15])[CH2:13][C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:7][C:6]2=[O:16])[CH2:25][CH2:24]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Cl
Product: O=C1CC2(CCCC2)CC(=O)N1CCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 4.9 g. (0.02 mole) of 8-[3-chloro-1-propyl)-8-azaspiro[4.5]decane-7.9-dione, 3.3 g. (0.02 mole) prepared in the manner of U.S. Pat. No. 3,398,151, N-(2-pyrimidyl)piperazine, and 2.2 g. (0.02 mole) of sodium carbonate in 75 ml. of n-butanol is refluxed for three days and filtered. The filtrate is concentrated in vacuo and the residue taken up in 100 ml. of benzene. Addition of 4.0 ml. of 5.0 N ethanolic hydrogen chloride to the benzene solution of the free base provides the product 8-[3-[4-(2-pyrimidinyl)-1-piperazinyl]propyl]-8-azaspiro[4.5]decane-7,9-dione as a hydrochloride salt which is collected and crystallized from absolute ethanol-ether, yield 3.4 g., m.p. 214°-215°C. (corr.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21]CC[CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B(O)O)=[C:28]([CH3:33])[O:27][N:26]=1.[C:34]([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[C:5]1(=[C:8]([C:16]2[CH:23]=[CH:22][C:21]([C:29]3[C:25]([CH3:24])=[N:26][O:27][C:28]=3[CH3:33])=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:34][CH2:4]1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 114.7 %

Procedure:
The procedure described for 202 was followed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.079 g, 0.56 mmol), Na2CO3 (0.060 g, 0.56 mmol), and THF/H2O (5 mL, 4:1). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (78%) of the title compound 206 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.28 (s, 1H), 7.28 (d, J=6.00 Hz, 2H), 7.18 (d, J=6.0 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.67 (d, J=6.3 Hz, 2H), 2.37 (s, 3H), 2.23-2.22 (br, m, s, 4H), 1.52 (br s, 8H). LCMS (ESI): m/z 372 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=O)[CH3:2].[S:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[S:17].C(O)(=O)C>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=[C:21]1[S:15][C:16](=[S:17])[NH:18][C:19]1=[O:20])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CCOc1ccc(C=O)cc1OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(C=C2SC(=S)NC2=O)cc1OCC

Procedure:
A solution of 10.0 g. of 3,4-diethoxybenzaldehyde, 6.86 g. of rhodanine, and 14.5 g. of fused sodium acetate in 70 ml. of acetic acid was heated to reflux for one hour. The hot mixture was poured into one liter of water with stirring. The resulting precipitate was col-lected by filtration and dried. Recrystallization from ethanol provided 10.22 g. of the subtitle intermediate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:28][C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Nc1ccccc1C
Yield: 58.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-phthalimidoquinoline (61.6 g, 0.16 moles) and o-toluidine (20 ml, 0.19 mol) was heated under reflux in 1,4-dioxan (300 ml) for 3 hours. The solvent was evaporated and the residue was dissolved in chloroform, washed with dil. ammonia solution and brine. The organic solution was dried (anhyd. MgSO4) filtered and evaporated to a dark oil which crystallized on standing to give 3-butyryl-4-(2-methylphenylamino)-8-phthalimidoquinoline (42 g, 58.3%), m.p. b 170°-2° C.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[Br:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1>ClCCl.C(OCC)C>[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[NH2:22]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)ccn1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nc1cc(Br)cc[n+]1N
Yield: 82.8 %

Procedure:
To a cooled suspension of O-(mesitylsulfonyl)hydroxylamine (11.22 g, 52.1 mmol, 1 eq) in dichloromethane (130 ml) is portionwise added 4-bromopyridin-2-amine (9.3 g, 52.1 mmol, 1 eq.) (exothermic reaction, some cooling is needed) giving a white suspension. After 1 hour the white suspension is diluted with diethyl ether (120 ml). The white solid is collected by filtration, washed with diethyl ether and dried affording 1,2-diamino-4-bromo-pyridinium 2,4,6-trimethyl-benzenesulfonate (16.74 g, 82.7%) as white crystals. mp.: 176-180° C. MS: m/z=188.2, 190.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].Cl[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1>CC(N(C)C)=O.O>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: N#Cc1ccc(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(Oc2cc(N)c(F)cc2Cl)cn1
Temperature: 25 °C

Procedure:
A solution of 5-amino-2-chloro-4-fluorophenol (100 mg, 0.619 mmol) in degassed dimethylacetamide (2 mL) was treated with potassium t-butoxide (83 mg, 0.743 mmol) and 5-chloro-2-cyanopyridine (86 mg, 0.619 mmol). The resultant mixture was heated to 80° C. overnight, then cooled to RT and diluted with water (10 mL). The mixture was extracted with EtOAc (30 mL). The organic phase was washed with water (3×30 mL) and brine (30 mL) dried (Na2SO4) and concentrated in vacuo to provide 5-(5-amino-2-chloro-4-fluorophenoxy)picolinonitrile as a dark oil which was used without further purification. MS (ESI) m/z: 264.0 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(OCC)=O>O>[C:25]1(=[O:34])[N:1]([CH:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([OH:12])=[O:11])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a stirred solution of d,l-phenylalanine (4.17 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carboethoxyphthalimide (5.65 g, 25.0 mmol). The resulting slurry is stirred for 1.5 hour and filtered. The pH of the filtrate is adjusted to 1-2 with 4N hydrochloric acid with stirring. After 20 minutes, the slurry is refiltered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 5.44 g (74%) of 2-phthalimido-3-phenylpropionic acid as a white powder: mp 165°-169° C.; 1H NMR (DMSO-d6, 250M Hz) δ12.5(br s, 1H), 7.84(s, 4H), 7.23-7.06 (m, 5H), 5.13 (dd, 1H, J=5.0), 3.26-3.05 (m, 2H); 13C NMR (250 MHz, (DMSO-d6) δ170.0, 167.0, 137.2, 134.8, 130.6, 128.6, 128.2, 126.5, 123.3, 52.8, 33.8. Anal. Calculated for C17H13NO4. Theoretical: C, 69.15; H, 4.44; N, 4.74. Found: C, 69.07; H, 4.34; N, 4.78.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[S:15][C:14]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)[CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[N:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A mixture of tert-butyl (S)-1-(5-(2-oxoindolin-5-yl)-1,3,4-thiadiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (350 mg) and TFA (10 mL) in DCM (10 mL) was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was partitioned between saturated sodium bicarbonate and DCM. The combined organic portions were washed with brine and then dried over sodium sulfate. Removal of the solvent gave the title compound 5-(5-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)indolin-2-one as an off-white amorphous solid (137 mgs, 48%). LCMS (API-ES) m/z (%): 434.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 3.05-3.16 (m, 2H) 3.54-3.64 (m, 3H) 3.68-3.76 (m, 1H) 3.90 (td, J=7.14, 4.30 Hz, 1H) 6.96 (d, J=8.22 Hz, 1H) 7.54 (d, J=8.02 Hz, 2H) 7.60-7.65 (m, 1H) 7.65-7.71 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C>[CH:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OC(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (100 g), anhydrous potassium carbonate (182 g) and 2-bromopropane (81 ml) in DMF (500 ml) was stirred at 65° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.