Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)=O.[CH2:25]([SH:29])[CH2:26][CH2:27][SH:28].Cl>C(Cl)(Cl)Cl>[S:28]1[CH2:27][CH2:26][CH2:25][S:29][CH:1]1[C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[S:29][CH2:25][CH2:26][CH2:27][S:28]3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: SCCCS
Reactant: O=Cc1ccc(OCCCCCCOc2ccc(C=O)cc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: c1cc(C2SCCCS2)ccc1OCCCCCCOc1ccc(C2SCCCS2)cc1
Temperature: -10 °C

Procedure:
A suspension of 52.55 g (0.16 mol) 1,6-bis(4-formylphenoxy)hexane, 200 ml chloroform and 34.85 g (0.32 mol) 1,3-propanedithiol was stirred in a 500-ml three-necked flask with gas-entry tube, reflux cooler, internal thermometer and magnetic stirrer and cooled to −10° C. Dry HCl gas was introduced for approx. 15 min, whereupon the suspension thickened markedly. After the introduction of the HCl was complete, the reaction mixture was stirred for another 30 min accompanied by ice-cooling, the ice bath was removed and the red-brown suspension was stirred for a further 2 h at room temperature. The solvent was then distilled off with a membrane pump (400 to 10 mbar) into a cold trap, 300 ml ethyl acetate and 100 ml methanol added to the residue and the reaction mixture stirred. The suspension was filtered, the solid residue washed with 100 ml methanol and 100 ml acetone and dried to constant weight in the vacuum drying cupboard. 78.2 g (96% of the theoretical value) 1,6-bis[4-(1,3-dithian-2-yl)phenoxy]hexane was obtained as a reddish, poorly soluble solid (m.p.: 189-192° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.CO>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A stirred mixture of 7-amino-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.7 g, 4.2 mmol) and cyclopropane carbonyl chloride (0.46 mL, 5.1 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. To the mixture was added methanol (4 mL) at room temperature and the mixture stirred for 10 min. The solvent was removed in vacuo to give an oil. The oil was recrystallized from ethanol (20 mL) to give cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as a white solid (1.4 g, 71% yield); mp, 172-174° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar) 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.87; H, 6.13; N, 6.12.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([F:21])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:21])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1F

Procedure:
Methyl 4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}-2-fluorobenzoate (Preparation 32, 3.6 g, 10.26 mmol, 1 eq) was suspended in 2.5M sodium hydroxide (16.5 ml, 41 mmol, 4 eq) and dioxane (4 ml) and the reaction mixture heated at 50° C. for 2 hours. The organic solvent was removed in vacuo and the residue diluted with ethyl acetate (20 ml). The remaining solid was removed by filtration and the organic layer separated. The aqueous phase was acidified with concentrated HCl, extracted into ethyl acetate, washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The title compound was obtained as a white solid (2.74 g, 8.1 mmol, 79%).
Reaction SMILES: Cl.[F:2][C:3]1[C:16]([F:17])=[CH:15][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:5]([O:18][CH3:19])[CH:4]=1.Br[CH2:21][CH2:22][NH:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:2][C:3]1[C:16]([F:17])=[CH:15][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:21][CH2:22][NH:23][C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:11][CH2:10]2)=[C:5]([O:18][CH3:19])[CH:4]=1
Reactant: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(F)c(F)cc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(F)cc1OCC1CCN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 90 °C
Yield: 41.5 %

Procedure:
5.88 g (0.020 mol) of 4-[(4,5-difluoro-2-methoxyphenoxy)methyl]piperidine hydrochloride, 7.7 g (0.021 mol) of 2-bromo-N-(triphenylmethyl)ethylamine and 6.91 g (0.050 mol) of K2CO3 in 40 ml of DMF are reacted. The reaction mixture is heated to 90° C. for 8 hours. It is cooled to room temperature, poured into 500 ml of water and extracted 3 times with ethyl acetate. The organic phases are combined, washed with water, dried over MgSO4 and filtered, and the solvent is evaporated off under reduced pressure. The product is obtained in the form of an oil after chromatography. Yield: 41.5%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[K].Cl.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([OH:15])(=[O:13])=[O:14])[C:10]=1[OH:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Reactant: CO
Agent: Cl
Agent: [K]
Product: COC(=O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3,4-Dihydroxy-5-sulfobenzoic acid, monopotassium salt (10.0 g, 36.7 mmoles) was slurried in 300 ml of dry methanol, cooled to 0° C., and treated for five minutes with dry hydrogen chloride. The resulting solution was allowed to warm to room temperature and was stirred for 48 hours. The mixture was filtered and the volatile materials were removed in vacuo. The resulting solid was dried in vacuo at 60° C. to give the title compound, 8.51 g, m.p. 116° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[OH:13][C:14]([CH3:19])([CH3:18])[C:15](O)=O.[OH-].[Na+]>Cl>[OH:13][C:14]([C:19]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)([CH3:18])[CH3:15]
Reactant: CC(C)(O)C(=O)O
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(O)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 39.5 %

Procedure:
To a solution of 2,3-diaminobenzoic acid methyl ester (1.5 g, 9.2 mmol) in 4 M HCl (50 mL) was added 2-hydroxyisobutyric acid (2.87 g, 27.6 mmol). The mixture was stirred at ˜90° C. for 24 h. It was neutralized by use of aqueous sodium hydroxide solution to pH˜3, and concentrated to dryness. The residue was suspended in methanol, and filtered through a filter paper. The filtrate was concentrated and the residue was rinsed with ether. The remaining solid residue was dissolved in ethyl acetate, and washed with brine solution. After drying over MgSO4, the organic solution was evaporated in vacuo, yielding the title intermediate as a pale yellow oil (˜800 mg). The crude product was used in the next step without further purification. (m/z): [M+H]+ calcd for C11H12N2O3 221.09; found 221.1. 1H-NMR (CD3OD) δ (ppm) 7.8 (dd, 1H), 7.7 (dd, 1H), 7.2 (m, 1H), 1.3 (s, 6H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:16][CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>ClCCCl>[C:36]1([NH:35][CH2:16][CH2:17][CH2:18][C:19]2[CH:34]=[CH:33][C:22]([O:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(CCC=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCCNc3ccccc3)cc2)nc1
Yield: 8.2 %

Procedure:
Add sodium triacetoxyborohydride (0.1633 g, 0.7705 mmol) to a stirred solution of 6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide (0.1341 g, 0.4962 mmol), aniline (0.047 mL, 0.5158 mmol), and 1,2-dichloroethane (7 mL). Stir the reaction for 18 h at room temperature under nitrogen. Pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with dichloromethane (3×50 mL), dry the dichloromethane extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.6% concentrated ammonium hydroxide/6% ethanol/chloroform to yield 0.0142 g (8%) of 6-[4-(3-phenylamino-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=348.1 (M+1); 1H NMR (CDCl3): 8.58 (d, 1H), 8.16 (dd, 1H), 7.26-7.18 (m, 7H), 7.10-7.04 (m, 2H), 6.97-6.94 (m, 1H), 6.79-6.51 (m, 2H), 3.19 (t, 2H), 2.76 (t, 2H), 2.04-1.97 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12]Br)[CH2:8][CH2:9][O:10][CH3:11])[CH3:2].[P:18]([O:27]C(C)C)([O:23][CH:24]([CH3:26])[CH3:25])[O:19][CH:20]([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12][P:18]([O:23][CH:24]([CH3:26])[CH3:25])([O:19][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:8][CH2:9][O:10][CH3:11])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CCOC)NC=O
Product: CCOC(=O)C(C=C(CCOC)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
3.38 g (11.0 mmol) of 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) of triisopropyl phosphite (96%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:37][CH3:38])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([C:33]([O:35]C)=[O:34])[CH2:22]1.O.[OH-].[Li+].Cl>C1COCC1>[C:29]([O:28][C:26]([N:24]1[CH2:25][C@@H:21]([O:20][C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:37][CH3:38])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:12]3[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=3)[CH:8]=2)[CH2:22][C@H:23]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:30])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Temperature: 40 °C
Yield: 105.5 %

Procedure:
Compound 132 (20 g) was dissolved in THF (66 mL) at room temperature. Water (66 mL) was added, followed by lithium hydroxide (5 eq.) in one portion. The reaction mixture was heated at 40° C. for 3 hrs, cooled, acidified with 5M HCl, and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum to give compound 133 (20.57 g) as a yellow form in 99% yield and 96-97% purity.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:28])(=[O:27])[NH:11][C@H:12]([C:21](=[O:26])[N:22]([O:24][CH3:25])[CH3:23])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:5]=1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:29][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[S:10](=[O:27])(=[O:28])[NH:11][C@H:12]([C:21](=[O:26])[N:22]([O:24][CH3:25])[CH3:23])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]([OH:37])=[O:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(C)OC)c(OCc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(=O)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 36.3 %

Procedure:
To a solution of 3-benzyloxy-4-[(S)-2-tert-butoxycarbonyl-1-(methoxy-methyl-carbamoyl)-ethylsulfamoyl]-benzoic acid methyl ester (8.20 g, 15.3 mmol) in tetrahydrofuran (150 mL) at room temperature was added 1N lithium hydroxide (30.5 mL, 15.3 mmol). The reaction was stirred at room temperature for 3.5 h. The reaction was then diluted with ethyl acetate (300 mL) and acidified to pH 2 with 5% citric acid. The organic layer was then washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 3-benzyloxy-4-[(S)-2-tert-butoxycarbonyl-1-(methoxy-methyl-carbamoyl)-ethylsulfamoyl]-benzoic acid as a white foam (2.9 g, 100%). MS(ACI) m/z 521.1 (M−H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32]>>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:9]3[N:10]=[CH:11][CH:12]=[C:7]4[CH2:6][CH2:5][O:4][C:8]=34)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, white solid (119 mg, 95%), MS (ISP) m/z=503.2 [(M+H)+], mp 243.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH-].[K+].CN(N=O)C(N[N+]([O-])=O)=N.[C:16]([O:20][C:21]([NH:23][C@@:24]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:29][C:28](=[CH2:30])[C@@H:27]2[C@H:25]1[C@H:26]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(OCC)C.O.C(OCCOCCO)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[C:16]([O:20][C:21]([NH:23][C@@:24]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:29][C:28]2([CH2:3][CH2:30]2)[C@@H:27]2[C@H:25]1[C@H:26]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C=[N+]=[N-]
Reactant: C=C1C[C@@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@H]2[C@@H]1[C@@H]2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CCOCCOCCO
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC2(CC2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21

Procedure:
Prepare an ethanol free solution of diazomethane in diethyl ether from a solution of potassium hydroxide (3.2 g, 57 mmol) in water (5 mL), diethylene glycol monoethyl ether (4 mL) and diethyl ether (10 mL) and N-methyl-N′-nitro-N-nitrosoguanidine (5 g, 34 mmoles) in a mixture of diethyl ether (35 mL) and diethylene glycol monoethyl ether (15 mL). Take the resulting solution of diazomethane and add it portionwise over 60 minutes to a suspension of palladium acetate (20 mg, 89.1 μmol) in a solution of the previously prepared mixture of unreacted ditert-butyl (1S,2S,5R,6S)-2-(tert-butoxycarbonylamino)-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate and title compound (185 mg) in diethyl ether (2 mL). Once gas evolution has ceased, leave to stand for 30 minutes, filter and concentrate under reduced pressure to yield a yellow oil. Purify by mass guided HPLC (RT=6.4 minutes (UV), 6.37 minutes (MS); LC Column: Waters XBridge™ 30 mm×100 mm Sum; water w/0.1% formic acid; gradient: 28-62% acetonitrile w/0.1% formic acid in 1.35 minutes then 62-95% in 6.65 minutes, then held at 95% for 3.55 minutes. Column temperature: ambient; flow rate: 45 mL/minute) to yield the title compound as a colorless oil (55.3 mg, 130.6 μmol). MS (m/z): 446 (M+23).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3](O)=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([Cl:23])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCC(C)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methylundecanoic acid (0.40 g, 2.0 mmol) in anhydrous dichloromethane (20 ml) and a catalytic amount of DMF (approximately 0.02 ml) was added oxalyl chloride (0.4 mL, 4.6 mmol). The resulting mixture was stirred vigorously for 2 hours at room temperature. The organic solvent was evaporated under reduced pressure and the residue (80) was used in the next step.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]([O:8]CC)=O.[CH3:15][N:16]([CH3:30])[S:17]([C:20]1[CH:25]=[C:24]([N:26]=[C:27]=[O:28])[CH:23]=[CH:22][C:21]=1[Cl:29])(=[O:19])=[O:18]>O1CCCC1>[CH3:15][N:16]([CH3:30])[S:17]([C:20]1[CH:25]=[C:24]([N:26]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:27]2=[O:28])[CH:23]=[CH:22][C:21]=1[Cl:29])(=[O:19])=[O:18]
Reactant: CN(C)S(=O)(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To 30 ml of dried tetrahydrofuran (THF) cooled to -5° C. was added, under nitrogen, 3.6 g of sodium hydride as a 60% dispersion mineral oil. To the stirred slurry was added a solution of 10 g of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 30 ml of THF over a period of 30 minutes. After stirring at -5° C. for 1 hour, the reaction mixture was cooled to -65° C. and a solution of N, N-dimethyl-2-chloro-5-isocyanatobenzenesulfonamide (Example A-4 above) in 30 ml of THF was added dropwise maintaining the temperature below -60° C. The mixture was stirred at -65° C. for 2 hours and allowed to warm to room temperature. After stirring for 17 hours, solvent was removed using a rotary evaporator. About 50 ml of water was added to the residue. The resulting mixture was filtered to remove a small amount, of undissolved solid and the filtrate was acidified with hydrochloric acid. The resulting precipitate was filtered to give 13 g of the title compound as a beige solid, m.p. 281°-283° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:22][CH2:21][N:20]2[C:11](=[N:12][C:13]3[C:18]([C:19]2=[O:23])=[CH:17][CH:16]=[C:15]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:14]=3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I>CN(C=O)C>[F:32][C:28]1[CH:27]=[C:26]([C:25]#[C:24][C:15]2[CH:14]=[C:13]3[C:18]([C:19](=[O:23])[N:20]4[CH2:21][CH2:22][CH:8]([N:7]([CH3:36])[C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10][C:11]4=[N:12]3)=[CH:17][CH:16]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of tert-butyl-3-((3-fluorophenyl)ethynyl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-ylcarbamate (0.3 g, 0.67 mmol, 1 equiv) and NaH (64.3 mg, 2.68 mmol, 4 equiv) in DMF (15 mL) was added CH3I dropwise. After stirring at rt for 2 hours, the reaction mixture was quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 462 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:15][N:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O.CS(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:15][N:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C=NNc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: CC(C)(C)c1cc(NN=Cc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
2.2g of the ester obtained in Example 5 were refluxed with 3g of potassium hydroxide for 1 hour in 70ml of a 3:3:1 mixture of ethanol, dimethyl sulfoxide and water. The reaction mixture was poured into 140ml of ice water and adjusted to pH 2 with hydrochloric acid, whereupon the precipitate was filtered off in vacuo. After recrystallization from methanol, there were obtained 1.2g of the above compound, m.p. 208°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].C(Cl)CCl>CN(C=O)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([F:40])([F:41])[F:39])[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (0.15 g; 0.45 mmol) and 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (0.14 g; 0.45 mmol) in DMF (3 mL) was stirred overnight at rt. EDC (0.086 g; 0.45 mmol) was added and the mixture was heated to 90° C. for 1 h. The mixture was poured in water, extracted with DCM and the combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by column chromatography.