Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[O:16][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([O-:22])=O)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:47]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[O:16][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:54][CH2:53][CH2:52][N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:22])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: NCCN1CCCC1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc(-c2cccc(C(=O)[O-])c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1Nc2ccccc2/C1=C\c1ccc(-c2cccc(C(=O)NCCN3CCCC3)c2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (E)-3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoate (20 mg, 0.06 mmol) and HOBt (16 mg, 0.14 mmol) in NMP (0.5 mL) was added EDCI (22 mg, 0.12 mmol). The reaction was stirred at rt for 10 min and then added 2-(pyrrolidin-1-yl)ethanamine (0.05 mL) followed by DIEA (0.05 mL). The reaction mixture was stirred at rt for 1 h and diluted with H2O (10 mL). The mixture was extracted with EtOAc (3×20 mL), dried over Na2SO4 and concentrated. The crude was purified by RHPLC to give (E)-3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide. LCMS (ES): m/z 463 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3Cl)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C[O-].[Na+:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:38]
Reactant: O=C(NCC(F)c1ccc(Cl)cc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCC(F)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.122 g, 0.226 mmol) in methanol (2 ml) was added 0.5 M sodium methanolate in methanol (0.476 ml, 0.238 mmol), and the reaction was stirred overnight. The reaction was concentrated, taken up in dichloromethane and hexanes, and concentrated again to yield 122 mg of the title compound as a white solid (96.1% yield). MS (apci) m/z=537.7 (M−Na+2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O.[CH:15]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>C1COCC1>[CH:15]([C:18]1[CH:19]=[C:20]([NH:24][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL RBF, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO3 (aq., conc.) and then brine. The solution was dried over MgSO4, filtered, and concentrated to yield N-(3-isopropyl-phenyl)-4-methyl-3-nitro-benzamide as an orange oil that solidifies upon standing. MS m/z 299=[M+H]+. Calc'd for C17H18N2O3: 298.34.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH2:11]([O:13][C:14]([C:16]#[C:17][C:18](OCC)=O)=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C>[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[C:18]([Cl:1])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[N:10]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NNc1ccccc1F
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(Cl)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
In a flask were 2-fluorophenylhydrazine hydrochloride (12.2 g, 75 mmol), diethylacetylene dicarboxylate (12.8 g, 75 mmol), potassium carbonate (20.7 g, 150 mmol), and ethanol (200 ml) placed and the resulting slurry heated at reflux for 5 hours. The mixture was cooled to room temp, diluted with water (400 ml) and acidified carefully with 2M hydrochloric acid. The mixture was stirred for 2 h then the resulting suspended solid collected by filtration, washed with water (3×50 ml) and dried in vacuo giving 11.4 g of 5-Chloro-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester [U1]. 1H NMR (300 MHz., DMSO): δ 1.29 (3H,t), 4.25 (2H,q), 5.92 (1H,s), 7.34-7.60 84H,m), 11.90 (1H,s,br). LCMS (Method A): RT=1.75 min, (M+H)+=251.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[CH:7][C:8]2[C@@H:9]3[C@@H:17]([CH2:18][C:19](=O)[C:20]=2[CH:21]=1)[C@H:16]1[C@@:12]([CH3:27])([C@@H:13]([O:23]COC)[CH2:14][CH2:15]1)[CH2:11][CH2:10]3.CC(OI1(OC(C)=O)(OC(C)=O)[O:41][C:39](=O)[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34]C1=2)=O.O.[CH2:51](Cl)Cl>>[CH3:51][O:41][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C@@H:19]1[CH2:18][C@@H:17]2[C@H:9]([CH2:10][CH2:11][C@@:12]3([CH3:27])[C@H:16]2[CH2:15][CH2:14][CH:13]3[OH:23])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:21][C:20]1=2
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: ClCCl
Reactant: COCOc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OCOC)CC[C@@H]12
Solvent: O
Product: COCCCCCC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(O)CC[C@@H]23)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-6-one—Dess-Martin Periodinane (9.46 g, 22.3 mmol) is added portionwise to a solution of the compound from b) (7.0 g, 18.6 mmol) in 300 mL of CH2Cl2. The resulting reaction mixture stirred at room temperature for 3 hours. The mixture is poured into water and the layers are separated. The aqueous layer is extracted with CH2Cl2, and the combined organic extracts are washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give a gooey, brown solid. Purification by silica gel column chromatography (15%) EtOAc/Hex) affords the title compound as a pale yellow, viscous oil (6.0 g, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].[NH2:13][C:14]1[C:15]([C:22]([NH2:24])=[O:23])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]#[N:21]>>[C:20]([C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:22]([NH2:24])=[O:23])[C:14]=1[NH:13][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][CH2:1][CH3:2])#[N:21]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: N#Cc1ccnc(C(N)=O)c1N
Product: CCOc1ccccc1CNc1c(C#N)ccnc1C(N)=O

Procedure:
The title compound was prepared from 2-ethoxybenzoyl chloride and 3-amino-4-cyanopyridine-2-carboxamide (Preparation 12), following the procedure of Preparation 7, and was obtained as a colourless solid. (6.2%), m.p. 150°-152° C. Found: C,61.99; H,4.62; N,17.84. C16H14N4O3 requires C,61.93; H,4.55; N,18.06%.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[O:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>>[O:18]1[C:22]2([CH2:27][CH2:26][N:25]([C:3]3[N:4]=[C:5]([CH2:12][C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[NH:6][C:7](=[O:11])[C:8]=3[C:9]#[N:10])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: C1CC2(CCN1)OCCO2
Product: N#Cc1c(N2CCC3(CC2)OCCO3)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 544 mg (3.80 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane to give 65 mg (48% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[N:18]=[C:17](Cl)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2].Cl.Cl.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[N:18]=[C:17]([N:41]2[CH2:42][CH2:43][N:38]([C:36]3[CH:35]=[CH:34][C:33]4[O:29][CH2:30][O:31][C:32]=4[CH:37]=3)[CH2:39][CH2:40]2)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(Cl)n1
Reactant: c1cc2c(cc1N1CCNCC1)OCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(N2CCN(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
2-(6-Butyl-2-chloro-pyrimidin-4-ylamino)-4-methylpentanoic acid (3-ethoxypropyl)amide (10 mg), 1-benzo[1,3]dioxol-5-yl-piperazine dihydrochloride (25 mg), and N,N-diisopropylethylamine (50 μL) were stirred for 24 h in 1 mL methyl sulfoxide at 100° C. The solution was cooled to room temperature and diluted with ethyl acetate (30 mL), then washed 4 times with 30 mL aliquots of a saturated aqueous solution of sodium chloride. Semi-preparative HPLC followed by silica gel chromatography (gradient: 2–4% methyl alcohol in methylene chloride) provided 2.2 mg of 2-[2-(4-benzo[1,3]dioxol-5-yl-piperazin-1-yl)-6-butylpyrimidin-4-ylamino]-4-methylpentanoic acid (3-ethoxypropyl) amide. ESI-MS (m/z) 555 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[CH:15]([N:18]([CH:21]([CH3:23])[CH3:22])CC)([CH3:17])C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O.CN([CH:61]=[O:62])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:18]3[CH2:15][CH2:17][CH2:23][C@H:21]3[CH2:22][O:62][CH3:61])=[O:13])[S:10][C:3]=12
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (6.59 g, 30 mmole) in DMF (100 ml) were added diisopropylethylamine, (6 ml, 4.45 g, 34.4 mmole), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (16.16 g, 31 mmole) and S-(+)-2-(methoxymethyl)pyrrolidine (3.73 g, 32.4 mmole). The resultant reaction mixture was stirred at ambient temperature for 16 hours. The crude reaction mixture was poured into water (600 ml) and extracted with EtOAc (3×200 ml). The combined organic extracts were washed with water (4×200 ml), dried over Na2SO4 and concentrated, in vacuo, to give 8.8 g of an amber oil, which was purified by silica gel chromatography. Elution with Et2O:EtOAc (67:33) and evaporation of the appropriate fractions gave 6.89 g (74%) of an orange syrup. 1H NMR (DMSO-d6): δ8.62 (1H, d, J=5.0 Hz), 7.88 (1H, s), 7.35 (1H, d, J=5.0 Hz), 4.54-4.47 (1H, m), 3.93-3.75 (2H, m), 3.71-3.55 (2H, m), 3.37 (3H, s), 2.15-1.92 (4H, m). Anal. Calcd. for C14H15N2O2SCl: C, 54.10; H, 4.87; N, 9.01; S, 10.32; Cl, 11.41. Found: C, 53.96;
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7](C)[C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.Cl.O1CCOC[CH2:20]1>>[NH2:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[C:12]([CH3:20])[CH:13]=1
Reactant: C1COCCO1
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1[N+](=O)[O-]
Agent: Cl
Product: Cc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-acteylamino-2-methyl-3-nitro-benzoic acid (4.8 g, 20.2 mmol) and 6 M HCl (aq) (150 mL) in 120 mL dioxane was stirred for 15 min at 105° C. The mixture was cooled, filtered and washed with water.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:44]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Cl[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15]1
Reactant: ClCC1CC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC1CC1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A vigorously stirred mixture of 3-hydroxy-4-methoxybenzaldehyde (20 g, 131 mmol), chloromethylcyclopropane (18.2 mL, 197 mmol) and powdered potassium carbonate (27.3 g, 197 mol) in dimethylformamide (400 mL) was heated under an argon atmosphere at 80° C. for 9 h. The mixture was allowed to cool and was filtered through Celite. The filtrate was concentrated under reduced pressure, the residue was extracted twice with ethyl acetate, the organic extract was washed five times with saturated aqueous sodium carbonate and was dried (sodium sulfate). The solvent was removed in vacuo to provide an off-white solid (21.2 g, 78%): m.p. 67°-69° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1([CH:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[O:25])[CH2:21][CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([C:24]([NH:23][CH:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:21][CH3:22])=[O:25])=[CH:34][CH:33]=3)[CH:29]=[CH:30]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Example 28, using 4-nitrophenylsulfonyl chloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 464 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([O:13]CC=C)[C:6]=2[CH3:17].O.C(N(CC)[C:23]1[CH:28]=CC=C[CH:24]=1)C>>[F:1][C:2]1[C:3](=[O:18])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([CH2:28][CH:23]=[CH2:24])=[C:7]([OH:13])[C:6]=2[CH3:17]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc2c(C)c(F)c(=O)oc2c1C
Solvent: O
Product: C=CCc1cc2c(C)c(F)c(=O)oc2c(C)c1O
Yield: 55 %

Procedure:
A solution of 3-fluoro-4,8-dimethyl-7-allyloxycoumarin (1.56 g, 6.28 mmoles) in 20 mL of N,N-diethylaniline was deoxygenated with argon for 30 minutes and then was heated at reflux for 4 hours, while being purged by bubbling argon through the solution. The reaction mixture was chilled in ice, the resulting precipitate was collected by suction filtration and dried in vacuo. Recrystallisation from a mixture of methanol:water gave 0.859 g (55% yield) of 3-fluoro-4,8-dimethyl-6-allyl-7-hydroxycoumarin (3, R═F, R′=H) as a white solid: mp 163-164° C.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C1(C)C=CC=CC=1>[O:40]=[C:38]1[C:37]2[C:36](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:35](=[O:45])[N:39]1[C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 7 h
Yield: 244 %

Procedure:
To a stirred slurry of trans-tert-butyl 2-hydroxycyclohexylcarbamate (1.00 g, 4.64 mmol), PPh3 (1.34 g, 5.10 mmol) and phthalimide (1.50 g, 10.20 mmol) in a 2:1 mixture of toluene and THF (15 mL) was added diisopropyl azodicarboxylate (1.0 mL, 5.10 mmol) dropwise over a period of 1 h. Once the addition was complete, the mixture was stirred at about 0° C. for 7 h and was then warmed slowly to 7° C. over a period of 14 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (3.90 g). The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.O.O[N:15]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:36][C:37]1([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH:42]2[CH:38]1[CH2:39][NH:40][CH2:41]2.C(N(CC)CC)C>CN(C)C=O>[NH3:15].[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:40]1[CH2:41][CH:42]2[CH:38]([C:37]2([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH3:36])[CH2:39]1)=[O:12]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)C3Cc4ccccc4C3)CC21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
To a solution of 2-indane carboxylic acid (E. D. Bergmann and E. Hoffmann, J. Org. Chem., 1961, 26, 3555, 100 mg, 0.62 mmol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.88 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a white foam (117 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1C(=O)O
Solvent: CC#N
Product: COc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methoxybenzoic acid (6 g, 39.4 mmol) in 80 mL of acetonitrile was added N-bromosuccinimide (7.4 g, 41.4 mmol) in 20 mL of acetonitrile. The reaction mixture was warmed to ambient temperature and the mixture was allowed to stir for 16 hours. Additional N-bromosuccinimide (14.8 g, 82.8 mmol) was added and the reaction mixture stirred for an additional 48 hours. The mixture was quenched with 25 mL of H2O and the layers were separated. The aqueous layer was extracted with three 15 mL of portions of CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 50% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 248, 250 (M+NH4)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:16]=[CH:15][C:11](C(O)=O)=[C:10](C)[CH:9]=1>CN(C=O)C.C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:1]([C:2]([Cl:4])=[O:3])=[C:10]([CH3:11])[CH:9]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DMF (1 drop) and oxalyl chloride (0.44 ml, 5.0 mmol) are added to a stirred suspension of 4-bromo-2-methylbenzoic acid (0.90 g, 4.19 mmol) in dry DCM (10 ml). The reaction is stirred for 3 h at RT when a clear solution is obtained. The solvent is removed in vacuo to give the title product as an oil which crystallised. This is used in the next step without purification.
Reaction SMILES: Cl.[CH:2]1([NH:6][C:7]([C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][N:14]([CH2:19][C:20]([OH:22])=O)[CH2:13][CH2:12][C:11]=3[N:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3]1.[CH:23]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:2]1([NH:6][C:7]([C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][N:14]([CH2:19][C:20]([N:30]4[CH2:31][CH2:32][N:27]([CH:23]5[CH2:26][CH2:25][CH2:24]5)[CH2:28][CH2:29]4)=[O:22])[CH2:13][CH2:12][C:11]=3[N:10]=2)=[O:8])[CH2:3][CH2:4][CH2:5]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(O)CN1CCc2nc(C(=O)NC3CCC3)ccc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCC1)c1ccc2c(n1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {2-[(cyclobutylamino)carbonyl]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}acetic acid hydrochloride (37 mg, 0.11 mmol), 1-cyclobutylpiperazine (19 mg, 0.133 mmol), BOP (59 mg, 0.133 mmol) and TEA (0.075 ml, 0.532 mmol) in DCM (5 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (10 mL) and EtOAc (10 mL). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (10 mL), dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil. MS (M+1): 412.4; 1H NMR (δ, CDCl3): 8.11 (d, 1H), 7.94 (d, 1H), 7.43 (d, 1H), 4.53-4.61 (m, 1H), 3.75 (s, 2H), 3.58-3.66 (m, 4H), 3.45 (t, 2H), 3.40 (s, 2H), 3.04 (t, 2H), 2.92 (t, 2H), 2.63-2.76 (m, 1H), 2.36-2.46 (m, 2H), 2.25-2.32 (m, 6H), 1.63-2.06 (m, 6H).