Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:69]1([NH:74][CH2:75][CH2:76][C:77]#[N:78])[CH2:73][CH2:72][CH2:71][CH2:70]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:74]([CH2:75][CH2:76][C:77]#[N:78])[CH:69]2[CH2:73][CH2:72][CH2:71][CH2:70]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CCCNC1CCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CCCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.2 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.100 g), TBTU (0.080 g) and HOBt (0.034 g) in DMF (3 ml) was added DIPEA (0.087 ml) followed by 3-(cyclopentylamino)propionitrile (0.035 g) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was washed with water and extracted with ethyl acetate. The organic layer was dried with brine and MgSO4, filtered and concentrated to give the title compound (0.190 g) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:37]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:38])[CH2:17][CH2:18]1)=[N:7]2
Reactant: CC(C)N=C=O
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)NC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure P using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and isopropylisocyanate to give 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N-isopropylpiperazine-1-carboxamide. 1H NMR (DMSO-d6) δ ppm 1.07 (d, J=6.8 Hz, 6H), 2.08 (br s, 3H), 3.04-3.06 (m, 4H), 3.24 (br s, 4H), 3.46-3.50 (m, 4H), 3.68-3.70 (m, 4H), 3.78 (m, 1H), 6.26 (d, J=7.6 Hz, 1H), 6.49 (br s, 1H), 7.12-7.18 (m, 1H), 7.28-7.32 (m, 1H), 7.53 (s, 1H), 7.78 (d, J=2 Hz, 1H), 8.35 (s, 1H). Mass Spectrum (ESI) m/e=526.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:13])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[CH3:36][C:37]1([CH3:45])[C:39]([CH3:41])([CH3:40])[CH:38]1[C:42](O)=[O:43]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:13][C:42]([CH:38]2[C:39]([CH3:41])([CH3:40])[C:37]2([CH3:45])[CH3:36])=[O:43])[S:5][C:6]=1[N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: Cc1nc(N)sc1N1CCOCC1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)C2C(C)(C)C2(C)C)sc1N1CCOCC1

Procedure:
A mixture of 4-methyl-5-morpholin-4-yl-thiazol-2-ylamine (prepared using the method described in Christopher et al., Bioorganic and Medicinal Chemistry Letters 2004, 14(22), 5521-5525), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, and 2,2,3,3-tetramethylcyclopropanecarboxylic acid were processed using the method described in Example 58 to afford the title compound. MS (ESI+) m/z 324 (M+H)+.
Reaction SMILES: C1(CO[C:9]([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:22])[O:18][C:19]([CH3:21])([CH3:20])[CH:13]3[CH2:12]2)=[O:10])C=CC=CC=1.[F:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=C=O)=[CH:26][CH:25]=1>C(O)C.[C].[Pd]>[F:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][NH:29][C:9]([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:22])[O:18][C:19]([CH3:20])([CH3:21])[CH:13]3[CH2:12]2)=[O:10])=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)N2CCN(C(=O)OCc3ccccc3)CC21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC(=O)N2CCN(C(=O)NCc3ccc(F)cc3)CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
(Phenylmethyl)tetrahydro-3-oxo-1,1-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (0.12 g, 0.39 mmol) was dissolved in ethanol (10 mL). 10% Palladium carbon (12 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through Celite, the Celite was washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). 4-Fluorobenzyl isocyanate (0.20 mL, 1.6 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:9) to obtain the title compound (0.11 g, yield 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.CC(O)=[O:12].OO>O>[CH:5]1[CH:6]=[N+:1]([O-:12])[CH:2]=[C:3]([CH2:7][C:8]#[N:9])[CH:4]=1
Reactant: N#CCc1cccnc1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: N#CCc1ccc[n+]([O-])c1
Reaction time: 72 h

Procedure:
A solution of 3-pyridylacetonitrile (11 g, 93.1 mmol), HOAc (55 mL), and 30% H2O2 (17 mL) was heated at 95° C. overnight, and at room temperature for 72 hours. H2O (50 mL) was added to the reaction mixture and the resulting solution was concentrated. This was repeated with additional H2O (100 mL). Toluene (2×100 mL) was used to remove residual H2O, and the resulting white solid was dried under vacuum overnight affording a waxy white solid: mp 120-125° C.; MS(+)APCI m/z 135 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24]/[N:25]=[C:26](\[C:33]3[N:37]([CH3:38])[C:36](=[O:39])[O:35][N:34]=3)/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][NH:9][C:17]2[N:18]=[C:19]([CH2:23][O:24]/[N:25]=[C:26](/[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)\[C:33]3[N:37]([CH3:38])[C:36](=[O:39])[O:35][N:34]=3)[CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(/C(=N\OCc2cccc(N(CCC3CCCCC3)C(=O)OC(C)(C)C)n2)c2ccccc2)noc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(/C(=N\OCc2cccc(NCCC3CCCCC3)n2)c2ccccc2)noc1=O
Yield: 63.8 %

Procedure:
A solution of tert-butyl (2-cyclohexylethyl){6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (100 mg, 0.187 mmol, 1 eq.) in dichloromethane (5 ml) was treated with trifluoroacetic acid (0.144 mL, 1.867 mmol, 10 eq.) and refluxed overnight. The reaction was quenched by addition of NaHCO3 sat. aq. and extracted with EtOAc (3×20 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. After concentration, the residue was purified by chromatography on silica gel to give 3-[(Z)-[({6-[(2-cyclohexylethyl)amino]pyridin-2-yl}methoxy)imino](phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (52 mg, 63% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:29])[C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:37]1(B(O)O)[CH2:39][CH2:38]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:29])[C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]([C:30]3[CH:35]=[CH:34][C:33]([CH:37]4[CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]2c2ccc(Br)cc2)cc1
Reactant: OB(O)C1CC1
Product: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]2c2ccc(C3CC3)cc2)cc1

Procedure:
Using the compound obtained in Example 239 and cyclopropylboronic acid (0.066 g), and by the reaction and purification in the same manner as in Example 242, the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[O:4]1.[Cl:21][C:22]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:23]=1O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:28][C:26]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:11][CH2:12]3)[O:4]2)=[C:22]([Cl:21])[CH:27]=1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Reactant: Oc1ccc(Br)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1cc(Br)ccc1OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Reaction time: 13 h
Yield: 95 %

Procedure:
2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (compound 1, 50 gm, 0.18 mole) was dissolved in toluene (300 ml) at room temperature. To this 44 gms of 2-chloro-4-bromophenol in toluene (150 ml) was added at room temperature 28° C. in the presence of ParaToluenesulfonic Acid (PTSA, 3.5 gm). Reaction mixture was refluxed with stirring for 13 hrs. It was then cooled and filtered. The filtrate was given water wash to bring the pH to neutral. Toluene was removed under vacuum to obtain a thick brick red colored product 95% yield.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C([NH:15][CH2:16][CH2:17][SH:18])(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].Cl.CCOC(C)=O>CC#N.CCOC(C)=O>[NH2:15][CH2:16][CH2:17][S:18][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7]
Reactant: O=C1OCCC1Br
Reactant: CC(C)(C)OC(=O)NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCCSC1CCOC1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
3-Bromo-dihydro-furan-2-one (2.49 g, 15.1 mmol) and 2-(Boc-amino)ethanethiol (2.9 g, 16.5 mmol) were dissolved in 40 mL of CH3CN. Then K2CO3(4.14 g, 30 mmol) was added to the solution. Let it stir at 80° C. for 16 h. The solvent was evaporated to dryness and the residue was purified by column chromatography (PE/EtOAc=4/1) to 3.8 g of BOC protected Intermediate 29 as colorless oil. The previous compound (3.7 g, 14.16 mmol) was dissolved in 10 ml of EtOAc. Then 40 mL of 4N HCl/EtOAc was added to the solution. Let it stir at 25° C. for 2 h. The white solid was filtered and washed with PE to give 2 g of Intermediate 29.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:30]1[CH:46]=[CH:45][C:33]2[N:34]=[C:35]([NH:37][CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[S:36][C:32]=2[CH:31]=1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:30]2[CH:46]=[CH:45][C:33]3[N:34]=[C:35]([NH:37][CH2:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[S:36][C:32]=3[CH:31]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)cc1
Reactant: Brc1ccc2nc(NCC3CCCCC3)sc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NCC5CCCCC5)sc4c3)cnc2Cl)cc1
Temperature: 85 °C

Procedure:
A reaction tube was charged with N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (157 mg, 0.369 mmol), 6-bromo-N-(cyclohexylmethyl)benzo[d]thiazol-2-amine (80 mg, 0.246 mmol), Pd(PPh3)4 (14.2 mg, 0.012 mmol), 2.0 M aqueous sodium bicarbonate (0.246 mL, 0.492 mmol) and 0.98 mL ethanol. The tube was sealed and the mixture was heated at 85° C. for 2.5 h. The reaction was concentrated, dissolved in 90/10 CH2Cl2/MeOH and passed through a silica plug. The filtrates were concentrated and the crude material was purified by reverse phase chromatography to provide N-(2-chloro-5-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide as a slightly yellow solid (7 mg, 5.2%). MS (ESI pos. ion) m/z calc'd for C21H27ClN4O3S2: 543.1/545.1. found 543.0/545.0.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:43])([F:44])[F:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a white solid required compound (633 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5](=[O:8])[CH2:6]Br)([CH3:3])[CH3:2].[C:17]1(N)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5](=[O:8])[CH2:6][NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-Isopropyl-N-(4-methoxy-phenyl) bromoacetamide (257.6 g, 924 mmol), 1,2-phenylene diamine (100 g, 924 mmol) and potassium carbonate (128 g, 924 mmol) in DMF (1200 mL) is stirred at 0° C. for 2 h and then allowed to stir at RT for 20 h. The reaction mixture is filtered through celite and the filtrate concentrated in vacuo The resultant residue is dissolved in EtOAc (1200 mL), washed with water (3×200 mL), brine (200 mL), dried (MgSO4) and concentrated in vacuo. After removal of about 70% of the solvent a precipitate formed which is removed by filtration and washed with cold EtOAc and dried to afford the desired product (67.1 g) as a beige solid. The combined filtrates were concentrated in vacuo to afford a dark oil (88 g). Two recrystallisations from ethanol afforded a second batch (29.6 g) of the desired product as a beige solid: 1H NMR (300 MHz, DMSO-d6), δ7.22 (m, 2H), 7.05 (m, 2H), 6.47 (m, 1H), 6.34 (m, 2H), 5.95 (m, 1H), 4.81 (m., 1H, J=6.8), 4.59 (dt, 1H, J=27.2, 6.1), 4.4 (s, 2H), 3.77 (s, 3H), 3.30 (s, 2H), 0.96 (d, 6H, J=6.8).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30]([O:32][CH3:33])=[O:31])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][CH:21]1[C:30]([O:32][CH3:33])=[O:31])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.11 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 3.51 ml of 4-methoxybenzyl mercaptan dissolved in 60 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 8.13 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine [prepared as described in step (7) above] in 20 ml of dry dimethylformamide was added dropwise to the mixture, which was then stirred at room temperature for 15 minutes and then at 40° C. for 4 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water, dried and freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 15:1 by volume mixture of benzene and ethyl acetate), to afford 6.89 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[N:31]=[C:32]=[O:33]>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([S:13][C:32]([NH:31][C:27]2[S:26][CH:30]=[CH:29][N:28]=2)=[O:33])=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S)cc1-c1ccccc1
Reactant: O=C=Nc1nccs1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(SC(=O)Nc2nccs2)cc1-c1ccccc1

Procedure:
A solution of 2-phenyl-4-mercaptobenzoyl-methionine methyl ester from example 12E or 12F (1.0 mmol) and the isocyanate prepared in example 29A (1.0 mmol) in THF is refluxed until TLC shows no thiol left. The solvent is then evaporated in vacuo, and the residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=1.542 min, m/z=430.23; 1H NMR (CDCl3) 1.02-1.15 (d, 6H), 1.50 (d, 3H), 2.09-2.21 (m, 6H), 2.32 (m, 1H), 2.78 (m, 1H), 5.65 (m, 1H), 6.98 (d, 2H), 7.15-7.30 (m, 6H), 7.55 (m, 1H), 7.70 (d, 1H), 8.60 (d, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([O:23][C:24]([CH3:28])([CH3:29])[C:25]([NH2:31])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OC(C)(C)C(=O)O)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OC(C)(C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
To a solution of 2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionic acid (96 mg, 0.24 mmol) in DMF (3 mL) was added HATU (184 mg, 0.48 mmol), ammonium chloride (39 mg, 0.72 mmol) and triethyl amine (100 μL, 0.72 mmol) and the reaction mixture stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water, extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to reverse phase preparative HPLC (C-18, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield 429 as a white solid (38 mg, 38%). LCMS: RT=7.36 min, [M+H]+=398; 1H NMR (400 MHz, d6-DMSO) 8.99 (1H, s), 8.11 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.16 (1H, s), 6.89 (1H, s), 6.37 (1H, s), 5.89 (1H, sept, J=6.6 Hz), 4.59-4.42 (4H, m), 1.54 (6H, s), 1.44 (6H, d, J=6.6 Hz)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[C@H:40]([OH:41])[CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[C@H:40]([OH:41])[CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.