Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][C:22]#[CH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][C:22]#[CH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOCC(=O)Cl
Reactant: C#CCNc1c(N)c(Cl)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Reaction time: 2 h
Yield: 79 %

Procedure:
Ethoxyacetyl chloride (89%, 28 g, 0.20 mol) was added dropwise to a solution of 2-chloro-N4-prop-2-ynylquinoline-3,4-diamine (43.5 g, 0.188 mol) and triethylamine (39 mL, 0.28 mol) in dichloromethane (600 mL) at 6° C. After two hours, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous layer was back-extracted with dichloromethane three times. The organic layers were combined and washed twice with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid was triturated with toluene with heating. A fine tan solid was isolated by filtration, rinsed with diethyl ether, and dried to yield N-[2-chloro-4-(prop-2-ynylamino)quinolin-3-yl]-2-ethoxyacetamide (47.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Temperature: 200 °C
Yield: 74.6 %

Procedure:
A mixture of 85 (0.7 g, 2.4 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 Hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried and concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.5 g, 75%): Mp=184-186° C.; 1H NMR (DMSO-d6) δ 10.04 (s, 1 H), 7.77 (d, 2 H, J=8.3 Hz), 7.67 (t, 1 H, J=0.8 Hz), 7.48-7.46 (m, 1 H), 7.26 (s, 1 H), 6.90 (d, 2H, J=8.2 Hz); MS 277/279 [M−H]−
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1)([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[S:10]1(=[O:11])(=[O:12])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:14]=[CH:13][C:7]=2[CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)C=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)S(=O)(=O)CC2
Yield: 121.9 %

Procedure:
A solution of 6-nitro-1-benzothiophene 1,1-dioxide (1.04 g) in acetic acid (50 ml) and ethyl acetate (50 ml) was hydrogenated over (10% palladium on carbon (130 mg, 50% wet). The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and washings were evaporated under reduced pressure to give the title compound (1.1 g). LCMS RT=1.50 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]1[S:13][C:14]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1)=[O:28]
Reactant: COc1ccc(Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc([N+](=O)[O-])cc3s2)cc1OC

Procedure:
The title compound was synthesised from (3,4-Dimethoxy-phenyl)-(6-nitro-benzothiazol-2-yl)-amine and 2,4-dichlorobenzoyl chloride (commercially available) according to the procedure described for Example 2. MS (m/e): 504.1 (MH+, 100%).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]1[N:5]=[CH:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:24]=[CH:23][C:16]([C:17](N(OC)C)=[O:18])=[CH:15][CH:14]=3)[C:8]=12.[Cl-].[NH4+]>O1CCCC1>[CH:4]1[N:5]=[CH:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([C:17](=[O:18])[CH3:1])=[CH:23][CH:24]=3)[C:8]=12
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C2OCCn3cncc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2OCCn3cncc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 mmol of methylmagnesium bromide solution (3M in diethyl ether) are added to a solution of 0.97 mmol of 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-N-methoxy-N-methylbenzamide in 10 ml of absolute tetrahydrofuran under argon. The reaction solution is stirred at room temperature for 4 hours and then poured into saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic phases are dried over magnesium sulphate and evaporated. The title compound is obtained as a beige solid from the residue by flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[Si:49]([O:56][C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50].N(C(N(C)C)=O)=NC(N(C)C)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:52]([Si:49]([CH3:51])([CH3:50])[O:56][C:57]1[CH:62]=[CH:61][C:60]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:59][CH:58]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: OCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of Compound 2 (2.8 g, 5.8 mmol) in toluene (10 ml), a solution of tributylphosphine (1.17 g, 5.8 mmol) in toluene (2 ml) was added at room temperature; this was followed by stirring for 1 hour. This was gradually added to a solution of Compound 18 (1.1 g, 4.9 mmol) and 1,1′-azobis(N,N-dimethylformamide) (1.0 g, 5.8 mmol) in toluene (10 ml), and this was followed by overnight stirring at room temperature. Ethyl acetate was added; the resulting insoluble matter was removed by Celite filtration, and washing was conducted with ethyl acetate. The combined organic phases were concentrated under reduced pressure; the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 2:1)) to yield Compound 21 (colorless oil 2.03 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:29])[N:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2ccccc2-c2n[nH]c(=O)o2)nc2cc(Br)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)oc1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a round bottom flask is added 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3H-[1,3,4]oxadiazol-2-one (100 mg, 0.242 mmol) in DMF (4 mL) at 0° C., followed by the addition of NaH (19 mg, 0.475 mmol). The reaction mixture is stirred at 0° C. for 10 minutes, followed by the addition of MeI (103 mg, 0.726 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (20 mL). The organic layer is separated, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-5% MeOH/CH2Cl2 as the eluent to afford 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3-methyl-3H-[1,3,4]oxadiazol-2-one (92 mg, 89%) as a solid. LCMS (ESMS): m/z 427.63, 429.67 (M++1).
Reaction SMILES: Cl[C:2]1[N:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:8]=1)=[O:5].[NH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][NH:37]2)=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>Cl>[NH:37]1[C:38]2[C:34](=[CH:33][CH:32]=[C:31]([NH:30][C:2]3[N:29]=[CH:28][CH:27]=[CH:26][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:8]=3)=[O:5])[CH:39]=2)[CH:35]=[N:36]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1)c1cccnc1Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1)c1cccnc1Nc1ccc2cn[nH]c2c1
Temperature: 155 °C

Procedure:
2-Chloro-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide (2.95 g) was dissolved in a small volume of IpOH. 6-amino indazole (2.75 g) and 0.53 mL of TFA were added. The reaction mixture was heated to 155° C. in an open flask for 3.5 h. After cooling to RT the residue was dissolved in 2 N HCl. The aqueous solution was extracted 2 times with CH2Cl2, basified to pH 12 by the addition of Na2CO3 and 1 N NaOH. The solution was extracted 6 times with CH2Cl2 to isolate the product. The combined 5 extractions were dried over Na2SO4, filtered and stripped. The crude product was purified by silica gel chromatography eluting with a step gradient of 3-5% MeOH:CH2Cl2 to yield the titled compound. MS: 525 (M+1) Calc'd for C27H27F3N6O2—524.5.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:34][S:35]([O:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:20])[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)(=[O:37])=[O:36]
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Oc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 36 was used to prepare the title compound from N-[7-hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H) and methanesulfonyl chloride (58 mg, 49%). TLC: Rf=0.38 in 10% MeOH/CH2Cl2, HPLC MS RT=2.05 min, [M+Na]+=551; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.18-2.30 (2H, m), 3.03-3.17 (2H, m), 3.28-3.37 (2H, m), 3.44-3.54 (2H, m), 3.60-3.75 (5H, m), 3.95-4.05 (2H, m), 4.19-4.29 (2H, m), 4.40 (2H, t), 4.56-4.66 (2H, m), 7.63 (1H, d), 7.82 (1H, dd), 8.29 (1H, d), 8.64 (1H, d), 8.93 (1H, dd), 9.35 (1H, s).
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[CH2:21]([NH:25][OH:26])[CH:22]([CH3:24])[CH3:23]>CO.Cl>[C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=[N+:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[O-:26])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)CNO
Agent: Cl
Solvent: CO
Product: CC(=O)Oc1c(C(C)(C)C)cc(C=[N+]([O-])CC(C)C)cc1C(C)(C)C
Yield: 52.3 %

Procedure:
To a solution of 4-acetoxy-3,5-di-tert-butylbenzaldehyde (17.0 g, 0.0615 mol) in methanol (250 mL) was added isobutylhydroxylamine (5.36 g, 0.0714 mol) and concentrated hydrochloric acid (10 drops). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (Rf=0.23 for product and 0.84 for starting material using 3:1 hexanes/EtOAc) The solvent was removed in vacuo and the residue was a red oil which when triturated with hexanes it turned into solid. The solid was separated and washed completely with hexanes. The titled compound was isolated in 52.3% yield as a white solid, m.p. 176.8-180.4° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[C:22]4[CH2:24][CH2:25][CH2:26][C:27](=[CH:30]N(C)C)[C:28](=O)[C:21]4=[CH:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.O.[NH2:42][NH2:43]>C(O)C>[C:34]1([C:19]2[CH:20]=[C:21]3[C:28]4=[N:42][NH:43][CH:30]=[C:27]4[CH2:26][CH2:25][CH2:24][C:22]3=[N:23][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NN
Reactant: CN(C)C=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Solvent: CCO
Solvent: O
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3CCC4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl(1-(4-(6-((dimethylamino)methylene)-5-oxo-3-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)phenyl)cyclobutyl)carbamate (90 mg, 0.17 mmol) in anhydrous ethanol (2 mL) was added hydrazine hydrate (25 μL, 0.5 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 99:1 to 60:40) and preparative HPLC (Method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O, 20 minutes run) to give the desired product as a white solid (50 mg, 58% yield). 1H NMR (500 MHz, CDCl3) 7.49 (s, 1H), 7.38 (d, 2H), 7.29 (d, 2H), 7.21-7.25 (br m, 5H+1H), 3.25 (m, 2H), 2.94 (t, 2H), 2.53-2.61 (br m, 1H), 2.42-2.52 (m, 2H), 2.31-2.41 (br m, 1H), 2.14-2.21 (m, 2H), 1.98-2.10 (m, 1H), 1.74-1.85 (m, 1H), 1.30-1.43 (br s, 9H). LCMS (Method A): RT=6.09 min, M+H+=507.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Oc1ccc(Br)cn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) in THF (12 mL) was added 2-hydroxy-5-bromopyridine (191 mg, 1.1 mmol) and triphenylphosphine (393 mg, 1.5 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (233 μL, 1.5 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (144 mg, 42%) as a colourless gum. MS: m/e=345.0/347.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:23].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]([O-:42])=[O:41].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:42][C:40](=[O:41])[CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][C:26]2[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:31])=[O:7])=[CH:4][C:3]=1[Br:23]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: Nc1c(Br)cc(C(=O)OCCCCCl)cc1CN1CCOCC1
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCOCC1

Procedure:
This compound was prepared from 4-(4-amino-3-bromo-5-morpholinomethyl-benzoyloxy)-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl[C:22]([C:24]([O:26][CH3:27])=[O:25])=[O:23]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22]([C:24]([O:26][CH3:27])=[O:25])=[O:23])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COC(=O)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)C(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 76.5 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added methyl (chlorocarbonyl)formate (0.49 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.55 g (76%) of product as an off-white solid: mp 247–249° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 10.81 (s, 1H), 8.59 (d, J=8.3 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 5.19 (dd, J=5.0 and 12.5 Hz, 1H), 3.91 (s, 3H), 2.98–2.85 (m, 1H), 2.68–2.50 (m, 2H), 2.14–2.09 (m, 1H); 13C NMR (DMSO-d6) δ 172.70, 169.63, 168.03, 166.45, 159.81, 154.57, 136.65, 134.93, 131.36, 124.67, 119.34, 117.17, 53.80, 49.06, 30.92, 21.94; Anal. Calcd. For C18H13N3O7: C, 53.49; H, 3.65; N, 11.70. Found: C, 53.53; H, 3.66; N, 11.52.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)[CH:2]=1.Cl.[CH:25]([O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31])([CH3:27])[CH3:26]>>[CH:25]([O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Reactant: CSCC[C@H](N)C(=O)OC(C)C
Agent: Cl
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)OC(C)C

Procedure:
The desired compound was prepared by coupling of 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid, prepared as in Example 228D with methionine isopropyl ester hydrochloride, prepared as in Example 229B using the procedure of Example 186C. 1H NMR (300 MHz, CD3OD) δ 8.70 (d, 1H), 8.46 (d, 1H), 8.31 (ddd, 1H), 8.01 (dd, 1H), 7.58 (m, 3H), 7.33-7.47 (m, 5H), 5.45 (s, 2H), 5.00 (heptet, 1H), 4.44 (m, 1H), 2.00-2.24 (m, 2H), 2.01 (s, 3H), 1.96 (m, 1H), 1.77 (m, 1H), 1.24 (d, 3H), 1.22 (d, 3H). MS (CI NH3) m/e 479 (M+H)+, 451, 419, 320, 288, 192. Anal calcd for C27H31ClN2O4S (+0.60 H2O): C, 61.67; H, 6.17; N, 5.33. Found: C, 61.67; H, 6.17; N, 5.33.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.[CH:9]([NH2:12])([CH3:11])[CH3:10]>C(O)C.C(O)CO>[CH:9]([NH:12][C:3](=[O:5])[CH:2]([F:1])[F:8])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(F)F
Reactant: CC(C)N
Solvent: CCO
Solvent: OCCO
Product: CC(C)NC(=O)C(F)F

Procedure:
A solution of 20 grams (0.16 mole) of ethyl difluoroacetate in 20 milliliters ethyl alcohol was added slowly in a solution of 9.5 grams (0.16 mole) isopropylamine amine and 5 drops of ethylene glycol in 30 milliliters ethyl alcohol. The temperature rose slowly to 27° C. The mixture was then refluxed for 3 days. After this reflux period, the solution was evaporated at 100 millimeters and the residue was distilled at atmospheric pressure to yield 18.0 grams, b.p. 86°-88°, identified by infrared spectroscopy as the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)CCC2
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of indane (50 mmol, 6.11 mL) in dichloromethane (50 mL) at 0° C. is added dropwise chlorosulfonic acid (200 mmol, 13.3 mL). The resulting solution is allowed to return to room temperature and stirred for 2 hrs. The solution is then poured slowly onto a mixture of ice (200 g) and dichloromethane (50 mL). The organic layer is separated, washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated to produce indan-5-sulfonic acid chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[CH2:27][NH:28][CH2:29][C:22]=12>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:29][C:22]=12
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1cnc2c(c1)CNC2
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3Cc4cccnc4C3)n2)c1

Procedure:
B48 was prepared following the general procedure reported for B10 using A1 and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride; yield: 92.2 mg (24%), dark amorphous solid. MS (ES) C17H17N7O2S requires: 383. found: 384 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19](O)=[O:20])=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][NH:30][C:19]([C:18]([NH:17][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:16])([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])[CH2:28][CH2:27]1
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Reactant: NCC1CC1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)NCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and cyclopropylmethanamine (CAN 2516-47-4) as starting materials. MS (EI): m/e=400.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:26])[CH2:18][N:19]1[CH:23]=[C:22]([CH:24]=O)[CH:21]=[N:20]1)[CH3:15].N1CCCC1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12]/[C:11](=[CH:24]\[C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:26])[CH:23]=2)/[C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cn1cc(C=O)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)Cn1cc(/C=C2\CN(C(=O)OC(C)(C)C)CC2=O)cn1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 34.8 %

Procedure:
To a solution of 1-(t-butoxycarbonyl)pyrrolidin-3-one (6.8 g) in ethanol (200 ml) were added ethyl(4-formyl-1H-pyrazol-1-yl)acetate (8.0 g) and pyrrolidine (600 μl). The resulting mixture was stirred at 80° C. for 45 minutes, cooled to room temperature, and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (4.47 g, yield: 35%).