Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[C:6]3[N:7]=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[CH2:13][CH2:14]1
Reactant: O=S1CCN(c2nc(Cl)nc3c(N4CCOCC4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(N4CCOCC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-morpholino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 232°-233° C.) and piperazine.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:7]1[CH:6]=[CH:5][C:4]([NH2:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(F)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 138 (25 g, 0.160 mol) in DMF (250 mL) at 0° C. was added dropwise a solution of NBS (28.5 g, 0.160 mol) in DMF (100 mL). The resulting mixture was stirred at 0° C. for 1 h and then at RT for another hour. After the completion of the reaction, the mixture was poured into water (4 L) and extracted with EtOAc. The combined organic layers were washed with water and brine solution, dried (Na2SO4), filtered and concentrated in vacuo to afford 34 g (90%) of 4-bromo-3-fluoro-2-nitro-phenylamine (140) as a yellow solid which was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].CN1C=CN=C1.[NH2:25][C:26]1[C:27]2[CH:47]=[CH:46][CH:45]=[CH:44][C:28]=2[C:29]2[CH:30]([CH2:42][Cl:43])[CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:33]=2[CH:34]=1>C(Cl)Cl>[C:38]([O:37][C:35]([N:32]1[C:33]2[CH:34]=[C:26]([NH:25][C:2]([O:4][CH2:5][CH:6]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)=[O:3])[C:27]3[CH:47]=[CH:46][CH:45]=[CH:44][C:28]=3[C:29]=2[CH:30]([CH2:42][Cl:43])[CH2:31]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(N)c1ccccc21
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(NC(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc21
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A solution of 9-fluorenylmethyl chloroformate (97%, 270 mg, 1.01 mmol) in dry CH2Cl2 (20 mL) was treated with 1-methylimidazole (90 mg, 1.10 mmol), followed by the above amine (270 mg, 0.84 mmol). The mixture was stirred at 20° C. for 1.5 h, then treated with additional 1-methylimidazole (18 mg, 0.22 mmol) and 9-fluorenylmethyl chloroformate (54 mg, 0.20 mmol). The mixture was stirred for a further 3 h and was then concentrated under reduced pressure, and the residue was chromatographed on silica gel. Elution with CH2Cl2 /petroleum ether (9:1) gave a solid that was recrysallized from iPr2O/petroleum ether to give give 3-(tert-butyloxycarbonyl)-1-(chloromethyl)-5-(9-fluorenylmethyloxycarbonylamino)-1,2-dihydro-3H-benz[e]indole (417 mg, 89%), mp 103-106° C. 1H NMR [(CD3)2SO] δ 9.73 (s, 1 H, NHCO2), 8.21 (br s, 1 H, H-4), 7.98 (d, J=8.5 Hz, 1 H, ArH), 7.95-7.85 (m, 3 H, ArH), 7.76 (br s, 2 H, ArH), 7.54 (t, J=7.5 Hz, 1 H, ArH), 7.48-7.27 (m, 5 H, ArH), 4.46 (d, J=7.0 Hz, 2 H, aliphatic H), 4.32 (t, J=6.8 Hz, 1 H, aliphatic H), 4.26-4.11 (m, 2 H, aliphatic H), 4.11-3.97 (m, 2 H, CHHCl, aliphatic H), 3.88 (dd, J=10.7, 6.9 Hz, 1 H, CHHCl), 1.52 (s, 9 H, C(CH3)3).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)=[O:5])C.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH3:22])([C:4]([OH:3])=[O:5])[CH2:7]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a −78° C. solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et2O. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[CH3:29]>>[I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:28]([C:30]4[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH3:29])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C(C)Cl)cn1
Reactant: COc1cc(Cn2cnc3cc(I)cnc32)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(C)Oc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 49.3 %

Procedure:
To a stirred mixture of 4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol (1.32 g, 3.46 mmol) and potassium carbonate (1.30 g, 9.41 mmol) in cetonitrile (25 mL) was added 5-(1-chloroethyl)-2-methoxypyridine (0.72 g, 4.20 mmol). The mixture was heated at 100° C. After 6.5 h, an additional quantity 5-(1-chloroethyl)-2-methoxypyridine (0.300 g, 1.75 mmol) was added, and heating was continued. After 22 h, the mixture was allowed to cool to room temperature and was partitioned between water and 1:5 ethyl acetate/diethyl ether. The phases were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (40 g SiO2 column, 0-10% 0.01 M ammonia in methanol/dichlormethane elute) afforded 0.88 g (49%) of 6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine as an impure solid.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([NH:18][S:15]([C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:6][CH:5]=2)[CH:10]=1)(=[O:17])=[O:16])(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NS(=O)(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45) (50 mg, 0.146 mmoles) in dichloromethane (5.0 ml) was added triethylamine (26 μl, 0.189 mmoles), dimethyl-pyridin-4-yl-amine (1 mg) and butyryl chloride (19 μl, 0.184 mmoles). After stirring for 16 hours at room temperature the reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 61 as an off-white solid (48 mg). LC/MS System C: Rt=3.82 mins, m/z (ES−)=412 ((M−H) for C22H23NO5S).
Reaction SMILES: [Cl-].[CH:2]1([CH2:6][NH2+:7][CH2:8][CH2:9]Cl)[CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]1[C:13]([CH3:21])=[C:14]([N:18]=[C:19]=[S:20])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:21])=[C:14]([N:18]=[C:19]2[N:7]([CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5]3)[CH2:8][CH2:9][S:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(Cl)cccc1N=C=S
Reactant: ClCC[NH2+]CC1CCC1
Agent: [Cl-]
Product: Cc1c(Cl)cccc1N=C1SCCN1CC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Br[CH2:18][CH2:19][CH2:20][F:21]>C1COCC1>[CH2:9]([O:8][P:6]([CH:11]([CH2:18][CH2:19][CH2:20][F:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:5][CH2:3][CH3:4])=[O:7])[CH3:10]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: FCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCF)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (2.72 g, 60% on mineral oil, 68.0 mmol) was washed several times with hexanes under an nitrogen atmosphere and was then suspended in dry THF (60 mL). Ethyl (diethoxyphosphoryl)acetate (13.3 g, 59.1 mmol) was added dropwise within 20 min at r.t. as a solution in dry THF (20 mL). After stirring for 2 h at r.t. 1-bromo-3-fluoropropane (10.0 g, 70.9 mmol) was added and the mixture was heated to reflux for 14 h. The mixture was then cooled to r.t. and the reaction was quenched by addition of sat. aq. ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine and dried over sodium sulphate. After evaporation of the solvent under reduced pressure the crude product was purified by column chromatography (silica, hexanes/ethyl acetate gradient).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:4]=1)[NH2:2].[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=O>C(O)(=O)C.C(O)C>[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[N:2][NH:1][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:4]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=NNc1cc(N3CCOCC3)nc(OCCN3CCOCC3)n1)C(=O)N2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Hydrazino-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (80 mg; ¼ mmol) was added to a flask along with 5-methylisatin (53 mg; ⅓ mmol) and ethanol (4 mL). One drop of acetic acid was added, and the reaction was stirred overnight at 60° C. The mixture was then filtered and the precipitate was washed with ethanol (1 mL) and dried to give 5-methyl-3-{[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono}-1,3-dihydro-indol-2-one.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][Cl:9].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[ClH:9].[ClH:1].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: ClCc1ccccn1
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(Cc4ccccn4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound A1 and 2-picolylchloride hydrochloride as described for compound 18. M.p. 214-216° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[Cl:11].Cl[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:17]2[S:18][CH2:14][CH2:15][N:16]=2)=[CH:6][C:5]=1[Cl:11]
Reactant: S=C=NCCCl
Reactant: COC(=O)c1ccc(N)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC2=NCCS2)cc1Cl

Procedure:
A mixture of 4-amino-2-chlorobenzoic acid methyl ester (0.5 g) and 2-chloroethylisothiocyanate (0.26 mL) in THF (20 mL) was refluxed for 24 h. THF was distilled and the residue was purified by column chromatography (silica gel: eluent: hexane/EtOAc 3:1-1:1) to yield 2-chloro-4-(2-thiazolinylamino)benzoic acid methyl ester (74 mg). ESMS: m/z 271 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=O)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1cc(F)ccc1NC2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1cc(F)ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 8-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Yield: 573.5 %

Procedure:
A mixture of the acid (8.56 g, 33.4 mmole) of Step E and p-toluenesulfonic acid monohydrate (1.05 g, 5.6 mmole) in methanol (70 mL) is refluxed for 2.5 hours (TLC, methanol-toluene 1:9). The methanol is evaporated and the residue is dissolved in ethyl acetate and washed with brine. After drying (MgSO4) the solvent is removed to yield a tan solid (8.68 g, 96.2%, m.p. 111°-113° C.). The crude product is used as such in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1)#N.[OH2:20].C(OCC)(=O)C.[OH2:27]>Cl>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:5]1[N:4]=[C:3]([C:1]([OH:27])=[O:20])[CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(Oc2cccc(C(F)(F)F)c2)n1
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-cyano-6-[3-(trifluoromethyl)phenoxy] pyridine (3.00 g, 0.011 mol) was suspended in about 15 ml of concentrated hydrochloric acid. The obtained suspension was stirred at about 100° C. for about 2 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([NH2:18])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25]>C(Cl)Cl>[CH2:24]([O:17][C:16](=[NH:18])[CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:25]
Reactant: CC1(CC(N)=O)OCCc2c1[nH]c1ccccc21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)CC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (20.0 g., 0.817 mole), described in Example 126, is dissolved in dry methylene chloride (400 ml) and freshly prepared triethyloxonium fluoroborate (17.00 g., 0.894 mole) is added in one portion to the solution. The reaction mixture is stirred at room temperature for 2 hr. The methylene chloride solution is washed with cold 30% aqueous potassium carbonate followed by brine and the dried organic layer is concentrated under reduced pressure. The residue is dissolved in ether (150 ml.). The solution is filtered and crystallization proceeds at room temperature to afford ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetimidate, m.p. 139.5°-141° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(N(CC)CC)C>CCO>[CH:13]1([NH:16][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])[CH2:15][CH2:14]1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: NC1CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1c(NC2CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
To a solution of 3,4-diethoxycyclobut-3-ene-1,2-dione (0.596 g, 3.5 mmol) in EtOH (5 mL) was added cyclopropylamine (0.2 g, 3.5 mmol), followed by triethylamine (0.49 mL, 3.5 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The title compound (0.13 g, 20%) formed as a white precipitate that was collected by filtration and washed with diethyl ether. LCMS (ES+) 182 (M+H)+, RT 1.42 minutes (method 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:4]=1[C:5](Cl)=[O:6])[CH3:2].[NH2:22][C:23]([NH2:25])=[NH:24].Cl>COCCOC>[NH2:24][C:23]([NH2:25])=[N:22][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:11][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(N2CCCCC2)c(S(C)(=O)=O)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: Cl
Solvent: COCCOC
Product: CCc1cc(N2CCCCC2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.6 g of 2-ethyl-4-piperidino-5-methylsulfonylbenzoyl chloride [obtainable by reacting 2-ethyl-4-chloro-5-methylsulfonylbenzoic acid with excess piperidine followed by chlorination with SOCl2 ] dissolved in 60 ml of ethylene glycol dimethyl ether are added dropwise to a solution of 8.7 g of guanidine in 60 ml of ethylene glycol dimethyl ether, and the mixture is stirred at 25° for one hour. 200 ml of ice-water are then added to the reaction mixture, which is acidified with 1N HCl, and subjected twice to extraction with 100 ml of ethyl acetate each time, and the organic phase is discarded. The aqueous phase is rendered alkaline with 1N NaOH and cooled. The product which precipitates is filtered off with suction to give N-diaminomethylene-2-ethyl-4-piperidino-5-methylsulfonylbenzamide, m.p. 218°-220°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)=[O:11])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To a mixture of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (12.9 g, 81.6 mmol), 4-fluorobenzenamine (9.06 g, 81.6 mmol, Alfa-Aesar) and HOAt (2.22 g, 16.3 mmol, Shanghai Medped Co. Ltd.) in DCM (80 mL) was added EDCI (18.76 g, 97.9 mmol, Shanghai Medped Co. Ltd.) in portions at rt. The reaction was warmed up to 45° C. and stirred for 3 h. The mixture was extracted with water (150 mL×5), followed by brine (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized in n-hexane to give the title compound as a pale yellow solid (12.83 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2.[C:22]1([S:28]([N:31]=C=O)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2
Reactant: O=C(c1ccccc1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-benzoyl-1,4-dihydroquinolin-4-one (0.57 g, 1.8 mmol) and benzenesulfonyl isocyanate (0.26 mL, 2.0 mmol) in acetonitrile (9 mL) and heat at reflux for 18 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel eluting with dichloromethane to obtain a solid. Recrystallize the solid from ethyl acetate/hexane to give the title compound; mp, 186°-187° C. Rf =0.37 TLC/silica gel/dichloromethane. Elem. Anal. Calcd. for C22H14Cl2 N2O3S: C, 57.77; H, 3.09; N, 6.13. Found: C, 57.76; H, 3.22; N, 5.91.
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH:9]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:10]=[C:11]2[CH2:20][NH:21][C:22](=[O:38])[C@H:23]([CH3:37])[NH:24][C:25](=[O:36])[C@H:26]([CH3:35])[NH:27]C(OC(C)(C)C)=O)(=[O:4])[CH3:3].Cl>C(OCC)C>[ClH:1].[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH:9]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH:10]=[C:11]2[CH2:20][NH:21][C:22](=[O:38])[C@H:23]([CH3:37])[NH:24][C:25](=[O:36])[C@H:26]([CH3:35])[NH2:27])(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2c(c1OC(C)=O)CC(c1ccccc1)C=C2CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc2c(c1OC(C)=O)CC(c1ccccc1)C=C2CNC(=O)[C@H](C)NC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
5,6-Bis(acetoxy)-1-(N-t-butoxycarbonyl-alanyl-alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene hydrochloride (2.00 g, 3.36 mmol) from Step 1 was dissolved in 25 mL of diethyl ether. The resultant solution was cooled and saturated with hydrogen chloride. The solution was stirred at ambient temperature for 3 h. The precipitate was filtered and washed thoroughly with dry diethyl ether. The solid was dried overnight at 60° C. in vacuo to give 1.69 g (95% yield) of the title compound as an off-white solid, m.p. 145°-161° C. (dec); 1H NMR (CDCl3) δ: 1.35 (dd, 3H), 1.41 (m, 3H), 2.23 (s, 3H), 2.26 (s, 3H), 2.70 (dt, 1H), 2.95 (dd, 1H), 3.69 (br s, 1H), 3.89 (dq, 1H), 4.17-4.45 (m, 3H), 6.11 (d, 1H), 7.07 (d, 1H), 7.25 (m, 6H), 8.27 (m, 1H). Analysis calculated for C27H33N3O6 +1.3HCl: C, 59.73; H, 6.37; N, 7.74. Found: C, 59.94; H, 6.08; N, 7.64.