Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[Cl:25][C:26]1[C:27](F)=[CH:28][C:29]([F:46])=[C:30]([S:32]([N:35]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=2)COC)(=[O:34])=[O:33])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[Cl:25][C:26]1[C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=2[CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:28][C:29]([F:46])=[C:30]([S:32]([NH:35][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=2)(=[O:34])=[O:33])[CH:31]=1
Reactant: COCN(c1ccc(F)cn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(F)(F)F)ccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccc(F)cn1)c1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2C2CCNCC2)cc1F
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 4-[2-hydroxy-5-(trifluoromethyl)phenyl]piperidine-1-carboxylate (Preparation 317, 51 mg, 0.15 mmol), 5-chloro-2,4-difluoro-N-(5-fluoropyridin-2-yl)-N-(methoxymethyl)benzenesulfonamide (Preparation 349, 50 mg, 0.1 mmol) and potassium carbonate (28 mg, 0.20 mmol) in anhydrous dimethyl sulfoxide (2 mL) was heated at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a light yellow thick oil, which was used in the next step without further purification. The residue was diluted with dichloromethane (2 mL), trifluoroacetic acid (210 uL, 2.7 mmol) was added and solution stirred at room temperature for 18 hours. The reaction solution was concentrated in vacuo and purified by preparative HPLC to afford the title compound as a white powder, 55.3 mg (as the trifluoroacetic acid salt)
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:16])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1ccc(C(=O)N2CCCC2)cc1
Reaction time: 0.03 h
Yield: 75.9 %

Procedure:
DIPEA (200 mg, 1.5 mmol) was added to a stirred solution of 4-(pyrrolidine-1-carbonyl)-benzoic acid (75 g, 0.34 mmol) in DMF (5 mL) followed by HOBt (50 mg, 0.37 mmol) and EDCI (164 mg, 0.85 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (127 mg, 0.37 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected to afford 130 mg (75.58% Yield) of N-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-4-(pyrrolidine-1-carbonyl)-benzamide. LC/MS [M+H]+: 504, 94.9%. 1H NMR (300 MHz, DMSO-d6): δ 7.2 (t, 1H), 7.96 (d, 2H), 7.64-7.48 (m, 3H), 7.36 (t, 3H), 4.9 (b, 1H), 4.2 (d, 2H), 4.0 (d, 2H), 3.5 (t, 2H), 3.4 (t, 2H), 2.1-1.8 (m, 6H), 1.7 (m, 3H).
Reaction SMILES: C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]1.Cl.[CH2:37]([O:44][C:45](=[O:49])[C@H:46]([CH3:48])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.C(Cl)Cl>[O:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]([NH:47][C@@H:46]([CH3:48])[C:45]([O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:49])=[O:35])[CH2:30][CH2:31]1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(O)CN1CCOCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49908.6 %

Procedure:
To DMTMM (76.1 g, 0.276 mol) and N-methylmorpholine (NMM; 32.9 mL, 0.300 mol) was added to a 0° C. solution of 2-morpholinoacetic acid (20.0 g, 0.138 mmol) and L-alanine benzyl ester hydrochloride (35.7 g, 0.166 mol) in DMF (100 mL) and DCM (200 mL). The reaction mixture was stirred for 4 h at ambient temperature then concentrated. EtOAc (500 mL) and water (500 mL) was added to the residue. The resulting two layers were separated and the aqueous phase was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×500 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=100:3) to afford (S)-benzyl 2-(2-morpholinoacetamido)propanoate (21.1 g, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]([F:13])([F:12])[F:11])[C:5]([Cl:14])=[C:4]([Cl:15])[C:3]=1[CH3:16].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:4]1[C:5]([Cl:14])=[C:6]([S:9][C:10]([F:12])([F:11])[F:13])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=1[CH2:16][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)c(Cl)c(SC(F)(F)F)c(Cl)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1c(Cl)c(Cl)c(CBr)c(Cl)c1Cl
Yield: 48.7 %

Procedure:
A mixture of 2,3,5,6-tetrachloro-4-trifluoromethylthiotoluene (13.46 g, 0.041 mol) and N-bromo-succinimide (7.26 g, 0.041 mol) in carbon tetrachloride (34 ml) was stirred and heated at reflux for 21 hours. After cooling the mixture was filtered and the liltrate washed with aqueous sodium hydroxide solution (5%, 2×100 ml), water (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness. Recrystallization of the residue gave 2,3,5,6-tetrachloro-4-trifluoromethylthiobenzyl bromide (8.17 g) m.p. 117°-118.5° C. as a white crystalline solid. By proceeding in a similar manner but by replacing 2,3,5,6-tetrachloro-4-trifluoromethylthiotoluene with the following starting material there was prepared:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]1>CN(C=O)C.O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[N:18]1[CH2:21][CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc3ccccc3n2)C1
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of Cs2CO3 (3.2 g, 10.0 mmol), 2-chloro-quinoline (0.8 g, 5.0 mmol) and tert-butyl azetidin-3-ylcarbamate (0.8 g, 5.0 mmol) was dissolved in DMF (20 mL) and the resulting mixture was heated to 100° C. overnight. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in petroleum ether) to give tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)carbamate (0.8 g, 2.9 mmol, 53% yield) as white solid. ESI-MS (M+1): 300 calc. for C17H21N3O2 299.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(CC(O)=O)(C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)CC(=O)O
Product: N#Cc1ccc(Cl)c(CBr)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
(Step 1) To a solution of 4-chloro-3-methylbenzonitrile (1 g) in t-butylacetic acid (10 ml) were added N-bromosuccinimide (1.5 g) and azobisisobutyronitrile (0.05 g), and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:1-1:9) to give 3-(bromomethyl)-4-chlorobenzonitrile (1.5 g) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)[C:14](OC)=[O:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(C)C)(C)C>C(O)(C)C>[CH2:1]([N:8]1[CH2:9][C:10](=[O:11])[NH:12][C@H:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[C:14]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(C)c1)NC(=O)CNCc1ccccc1
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: Cc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
A mixture of methyl (2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate (2.5 g) and acetic acid (0.2 ml) in isopropyl alcohol (8.8 ml) was stirred for 5 hours under reflux. After being cooled to room temperature, isopropyl ether was added to the mixture. The resulting precipitates were collected by filtration and washed with isopropyl ether to give colorless crystals of (3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.26 g).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][N:18](CCO)[CH:19]=2)[CH2:10][C@H:9]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[O:7].[CH2:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH3:42].CS([Cl:52])(=O)=[O:50]>C(OCC)(=O)C>[ClH:52].[ClH:52].[F:37][C:35]([F:38])([F:36])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:1])[F:40])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][N:18]([CH2:42][CH2:41][N:43]3[CH2:46][CH2:47][O:50][CH2:45][CH2:44]3)[CH:19]=2)[CH2:10][C@H:9]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cnn(CCO)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Solvent: CCOC(C)=O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CCN4CCOCC4)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Product: Cl
Reaction time: 0.17 h

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazine (152 mg) in ethyl acetate (2 ml) was added triethylamine (0.048 ml) and methanesulfonyl chloride (0.027 ml) at room temperature. After stirring for 10 minutes, the mixture was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was dissolved with N,N-dimethylformamide (2 ml) and added morpholine (0.028 ml), potassium carbonate (74 mg) and potassium iodide (13 mg). After stirring at 70° C. for 6 hours, the mixture was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate (0.2 ml) at room temperature. The mixture was added hexane, filtered, and dried over reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-morpholinoethyl)-1H-pyrazol-4-yl]methyl]piperazine dihydrochloride (188.7 mg) as a solid.
Reaction SMILES: Cl[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.[B:21]1([OH:31])[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[CH2:23][O:22]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[OH:31][B:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C:2]3[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=3)=[CH:29][C:24]=2[CH2:23][O:22]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(C(F)(F)F)cc1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A mixture of 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile (180 mg, 0.58 mmol), benzo[c][1,2]oxaborole-1,5(3H)-diol (87 mg, 0.58 mmol) and Cs2CO3 (228 mg, 0.7 mmol) in DMSO (20 mL) was stirred at 40° C. for 1 hr, the mixture was diluted by water, extracted by EtOAc, the organic layer was concentrated in vacuo and the residue was purified by prep. HPLC (column: Gemini 100×21.2 mm, 5 g; liquid phase: [A-H2O; B—CH3CN+0.4% NH4OH] B %:45%-65%, 15 min) to afford 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile (170 mg, 69%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.24 (s, 1H), 8.73 (s, 1H), 7.79-7.77 (d, 1H), 7.31-7.31 (d, 1H), 7.23-7.21 (q, 1H), 4.97 (s, 2H), 4.14-4.11 (t, 2H), 3.47-3.45 (t, 2H), 3.43-3.37 (m, 1H), 0.98-0.96 (d, 6H).
Reaction SMILES: [C:1]([N:8]([CH3:13])[CH:9]1[CH2:12][NH:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1>CC(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:13][N:8]([CH:9]1[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=2)[CH2:10]1)[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Reactant: Cc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(N2CC(N(C)C(=O)OC(C)(C)C)C2)ccn1
Yield: 51 %

Procedure:
3-(Boc-methylamino)azetidine (2.74 mmol, 1.0 eq) and 4-chloro-2-methylpyridine HCl (8.21 mmol, 3.0 eq) were dissolved in 2-propanol (5 ml) and DI PEA (13.69 mmol. 5.0 eq) and refluxed for 24 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate, concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 51%
Reaction SMILES: C(OC(O[C:9]1([O:13]/[N:14]=[C:15](/[C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)\[C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.C[CH2:26][OH:27].C1CCC1.CS(C)=[O:34]>>[C:26]([C:9]1([O:13]/[N:14]=[C:15](/[C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)\[C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:11][CH2:12]1)([OH:27])=[O:34]
Reactant: CCO
Reactant: CS(C)=O
Reactant: COC(=O)/C(=N\OC1(OC(=O)OC(C)(C)C)CCC1)c1ccco1
Agent: C1CCC1
Product: COC(=O)/C(=N\OC1(C(=O)O)CCC1)c1ccco1
Yield: 94 %

Procedure:
This compound was prepared from methyl Z-2-(1-tert-butyloxycarbonyloxycyclobutyloxyimino)-2-(fur-2-yl)acetate as described in Preparation 7(b), m.p. 133°-134°. λmax (EtOH) 284 nm (ε15,900), νmax (Nujol) 3500-2100 (bonded OH), 1750 (CO2H), 1708 cm-1 (α,β-unsaturated --CO2R), τ(DMSO d6) 7.2-8.5 (cyclobutane), 2.1, 3.12, 3.33 (furyl), 6.09 (--CO2CH3). Yield 94%
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.BrC1C=CC([CH2:18][S:19](CC2C=CC(Br)=CC=2)(=[O:21])=[O:20])=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]1N>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:43]3[CH:42]=[CH:41][C:40]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:39][CH:44]=3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=S(=O)(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2ccc3cnc(Cl)nc32)cc1
Temperature: 110 °C

Procedure:
In a seal tube, 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 3.56 mmol), 4-bromophenylmethylsulfone (700 mg, 4.10 mmol), CuI (239 mg, 1.23 mmol), and K3PO4 (2.67 g, 12.3 mmol) are suspended in 1,4-dioxane (30 mL). Then, trans-1,2-diaminocyclohexane (149 μL, 1.23 mmol) is added at rt. The reaction vial is flushed with Ar and the mixture is heated to 110° C. for 3 h. After cooling to rt, the reaction mixture is concentrated under reduce pressure. The residue is suspended in EtOAc and washed with saturated aqueous NaCl solution (3×). The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The solid residue is triturated with small amounts of EtOAc to yield the title compound as a brown solid.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCCl.[C-:14]#[N:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:3]1([CH:2]([OH:9])[CH2:1][C:14]#[N:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: N#CCC(O)c1ccccc1

Procedure:
The procedure of Experiment 1 was repeated employing 1.0 g of racemic styrene oxide, 4 ml of 1,2-dichloroethane, 2 ml of water, 596 mg of potassium cyanide, and 267 mg of tetrabutylammonium bromide. After 6 hours of heating at reflux, the reaction mixture was cooled and worked up extracting with methylene chloride. Proton nuclear magnetic resonance analysis indicated the desired product contaminated with the phase transfer catalyst.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]([O:34][C:32]([NH:31][CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[O:33])([CH3:37])[CH3:36]
Reactant: Cc1sc(N2CCOCC2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(N2CCOCC2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 3-{2-(isopropoxycarbonylamino-methyl)-4-[2-(5-methyl-2-morpholin-4-yl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid tert-butyl ester (387 mg, 0.706 mmol) in CH2Cl2 (10 mL) was treated with anisole (1 mL) then TFA (3 mL). The solution was stirred at room temperature for 2 h and concentrated. The residue was co-evaporated with CCl4 twice, dried under vacuum, triturated with ether, and filtered to obtain the title compound as a white solid (236 mg, 60%), isolated as the trifluoracetic acid salt: 1H NMR (400 MHz, CDCl3) δ 1.12 (d, 6H, J=6.4 Hz), 2.16 (s, 3H), 2.47 (t, 2H, J=7.6 Hz), 2.79 (t, 2H, J=7.6 Hz), 2.87 (t, 2H, J=6.4 Hz), 3.35 (t, 4H, J=4.9 Hz), 3.70 (t, 4H, J=4.9 Hz), 4.07 (t, 2H, J=6.6 Hz), 4.23 (d, 2H, J=5.4 Hz), 4.82 (heptet, 1H, J=6.1 Hz), 5.07 (bs, 1H), 6.63 (dd, 1H, J=2.7, 8.6 Hz), 6.69 (d, 1H, J=2.9 Hz), 6.98 (d, 1H, J=8.3 Hz). MS (ES) m/e 492.1 [M+1].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: Oc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1)c(=O)oc(=O)n2C
Product: CNc1ccc(OC)cc1C(=O)n1nc(O)c2ccccc21
Yield: 40.6 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-5-methoxy isatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 40.6% yield; m.p. 161°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@H:11]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[S:27][C:26]2[NH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[N:22]=[C:21](N)[C:20]=2[N:19]=1.CN1CCCC1=O>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C@@H:11]2[NH:12][CH2:13][CH2:14][N:15]([C:21]3[C:20]4[N:19]=[C:18]([CH3:17])[S:27][C:26]=4[NH:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[N:22]=3)[CH2:16]2)=[CH:7][CH:8]=1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: COc1ccc(CC[C@H]2CNCCN2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C)nc43)CCN2)cc1
Temperature: 195 °C
Reaction time: 3.75 h
Yield: 109.1 %

Procedure:
Combine (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (180 mg, 0.82 mmol), 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (188 mg, 0.82 mmol), 1-methyl-2-pyrrolidinone (5 mL). Heat at 195° C. After 3.75 h, cool to ambient temperature and stir 18 h. Combine with another 2.30 mmol reaction executed under same conditions. Dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%–4%) as the eluent to give 388 mg (29%) of the title compound: mass spectrum (ion spray): m/z=434 (M+1), 432 (M−1). HR-MS calculated for C24H28N5OS: 434.2015. Found 434.201 HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([N:17]3[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]3)[CH2:7][C:6]2=1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([N:17]3[CH:21]=[C:20]([NH:22][C:34]([C:31]4[CH:32]=[CH:33][C:27]5[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=5[CH:30]=4)=[O:35])[CH:19]=[N:18]3)[CH2:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(n1cc(N)cn1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1)CC(n1cc(NC(=O)c2ccc4c(c2)NC(=O)CS4)cn1)CO3

Procedure:
The titled compound is prepared as a white solid (95 mg, 58% yield) following Scheme 3 and in analogy to Example 1 using 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-1H-pyrazol-4-ylamine (100 mg, 0.34 mmol, 1.0 eq) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (85 mg, 0.40 mmol, 1.2 eq) as starting materials.