Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39](Cl)(=[O:41])=[O:40]>N.CO>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1ccc2ccccc2c1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Naphthalene-2-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.2 mg). MS m/z 379 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (41 mg) and morpholine (53 mg) were suspended in N,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (34 mg, yield 69%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.ClCCl.[Cl:15][C:16]1[C:21]([CH:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=1>CCOCC>[Cl:15][C:16]1[C:21]([C:22]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: OC(c1cccnc1Cl)C1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
Pyridinium chlorochromate (20.0 g, 93 mmol) was added to a dichloromethane (200 ml) solution of 2-chloro-α-cyclohexyl-3-pyridinemethanol (17.0 g, 75 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was mixed with pyridinium chlorochromate (10.0 g, 46 mmol) and stirred for 2 hours at room temperature, and then ether was added to the reaction solution to remove insoluble matter by filtration. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-chloroform) to give 2-chloro-3-cyclohexylcarbonylpyridine (14.9 g, 88%) as an oily material.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[C@H:3]([NH:8][C:9](=[O:42])[C@@H:10]([CH2:18][C@@H:19]([OH:41])[CH2:20][S:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4](=[O:7])[NH:5][CH3:6].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:43][C:2]([CH3:1])([CH3:44])[C@H:3]([NH:8][C:9](=[O:42])[C@@H:10]([CH2:18][C@@H:19]([OH:41])[CH2:20][SH:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4](=[O:7])[NH:5][CH3:6]
Reactant: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC[C@H](C[C@@H](O)CS)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 0.700 g (1.136 mmol) of the product of Example 33 and 0.363 mL (2.273 mmol) of triethylsilane dissolved in 10 mL of dichloromethane was dropwise added 10 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 0.5 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes (gradient: 1:3-1:1) to provide 0.263 g (62%) of the desired product as a colorless oil. Electrospray Mass Spec: 375.4 (M+H)+.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH-:7].[Na+]>>[Si:2]([O-:7])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: [OH-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
(Comparison) 1600 kg of water glass with an SiO2/Na2O ratio of 2.06 and an active substance content of 45.5% were admixed with 36.8 kg of sodium hydroxide solution (48% strength) and spray-dried in a spray tower from Kestner to give an amorphous sodium silicate having an active substance content of 83%. 15 kg of the amorphous sodium silicate are heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). A second batch is treated identically. The chilled materials (about 24 kg) are pulverized using a jaw crusher and a disk mill.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C=O)C>[CH2:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 14 h
Yield: 100.8 %

Procedure:
To a mixture of dimethyl 5-hydroxy-isophthalate (10 g, 47.577 mmol), Cs2CO3 (31 g, 95.2 mmol) in DMF was added allyl bromide (4.83 mL, 57.1 mmol) drop-wise. After stirring the mixture for 14 hours, the reaction was treated with water, extracted with EtOAc (2×). The combined organic extract was dried over sodium sulfate, filtered and evaporated to provide the desired product as white solid (12 g, 100% yield). The crude product was used without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 6 H) 4.56-4.71 (m, 2 H) 5.33 (dd, J=10.46, 1.41 Hz, 1 H) 5.39-5.53 (m, 1 H) 5.96-6.17 (m, 1 H) 7.76 (d, J=1.32 Hz, 2 H) 8.28 (t, J=1.41 Hz, 1 H); LC-MS: (ESI)+m/z=251.00 (M+1)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[CH2:1]([O:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccccn1
Product: c1ccc(COc2ccccn2)cc1

Procedure:
The synthesis of 1 is illustrated in FIG. 8. Benzyl alcohol is coupled with 2-chloropyridine using a modification of a reported procedure to afford 2-benzyloxypyridine, compound 5, in high yield. A range of alkylating agents and solvents was investigated in search of preferred conditions for the irreversible covalent activation of 5. The preferred protocol is to add methyl triflate (bp 94-99° C.) to an ice-cold solution of compound 5 in toluene and allow the mixture to warm to ambient temperature. A white microcrystalline solid, compound 1, forms within minutes, as the solution warms. Analytically pure compound 1 (mp 82-86° C.) can be isolated by filtration or by evaporation of the supernatant under reduced pressure. Salt 1 is remarkably stable. It may be preferably stored under an argon atmosphere either in a refrigerator or on the laboratory bench-top at room temperature and the white crystals of compound 1 are routinely handled open to the air. No differences have been observed between freshly prepared crystals and those that were prepared three months prior.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[Cu][C:42]#[N:43]>CN1CCCC1=O>[C:42]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[CH:14]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1)#[N:43]
Reactant: N#C[Cu]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccc(C#N)cc1
Temperature: 200 °C
Reaction time: 2.5 h

Procedure:
To a 20 ml microwave vial was added 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-bromophenyl)-ethyl]-amide (62 mg, 0.10 mmol), copper (I) cyanide (18 mg, 0.20 mmol), and N-methyl-pyrrolidinone (6 ml) (HPLC grade, dried with 4A powdered molecular sieves). The resulting solution was purged with nitrogen then the vial sealed, and heated in an oil bath at 200° C. After 2.5 h the reaction was allowed to cool to room temperature over 17 h. The reaction was separated into two vials and each was independently subjected to heating in a microwave reactor at 200-230° C. for 2.5 h. The reactions were combined, diluted with water (50 ml), and extracted with ethyl acetate (50 ml) two times (5 ml of brine was added to clear phases). The organic layers were washed with brine (25 ml), combined, dried over magnesium sulfate, filtered, and further dried under a stream of nitrogen. The crude brown solid was purified by flash chromatography (4 g silicycle) with 0% to 60% EtOAc in hexanes. The appropriate fractions were combined and dried from a mixture dichloromethane and hexanes yielding 32 mg (56%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-phenyl)-ethyl]-amide as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:26][CH3:27]>CN(C=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: CCI
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
A solution of 2A (1 g, 3.6 mmol) in DMF (15 mL) was added with an. K2CO3 (1.4 mol eq, 0.7 g) and, after few minutes, 2-iodoethane (1.2 mol eq, 0.45 ml) was added and the mixture heated at 50° C. for 5 h. The solvent was removed under reduced pressure, water was added to the residue (80 mL) and the aqueous phase extracted with EtOAc (3×30 mL). The combined organic phases were dried using Na2SO4 and evaporated under reduced pressure to obtain 3B as a pale yellow oil (1.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.13 (t, 3H, J=8), 3.29 (q, 2H), 3.41 (s, 3H), 3.79 (m, 2H), 4.53 (t, 1H), 5.14 (t, 1H), 7.41 (t, 2H, J=10), 7.86 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:17]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:41]([OH:52])(=O)[C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=O)=[CH:44][CH:43]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([CH3:10])[C:11]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:17]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:16]=2[N:15]([C:46]([C:45]2[CH:44]=[CH:43][C:42]([C:41]([N:15]3[C:16]4[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:17]=4[N:18]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][C:23]=4[CH3:32])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:40])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:10])[CH2:14]3)=[O:52])=[CH:50][CH:49]=2)=[O:48])[CH2:14]1)=[O:39])=[O:40])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(C)ccc5ccccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of {(S)-1-[(S)-7-cyano-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 16) (90 mg, 0.166 mmol) in pyridine (1 mL) was added terephthalic acid (13.808 mg, 0.083 mmol). After 10 min the mixture was cooled to 0° C., POCl3 (0.017 mL, 0.183 mmol) was added and the cooling bath was removed. After 1 h, the mixture was concentrated, the residue was dissolved in ethyl acetate and the mixture was washed with water, NaHCO3 solution, and brine, dried over sodium sulfate and concentrated. The residue was purified by preparative reverse phase HPLC to provide tert-butyl N-[(1S)-2-[[(3S)-5-[4-[(3S)-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzoyl]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate as white solid (5 mg, 5.32%). LC-MS: 1213.6 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(O)(=O)C.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH:16]=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=Cc1c(F)cccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1cccc(F)c1CNc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.1 %

Procedure:
To a solution of 6-bromopyridin-3-amine (500 mg, 2.89 mmol), in MeOH (3 mL), acetic acid (0.165 mL, 2.89 mmol), 2,6-difluorobenzaldehyde (0.31 mL, 2.89 mmol) was added. After stirring the resulting mixture at RT for 12 h, sodium cyanoborohydride (363 mg, 5.78 mmol) was added at 0° C. and resulting mixture was stirred at RT for 6 h. Solvent was evaporated under vacuum. Residue was purified by column chromatography to afford 200 mg (23%) of the title compound as white solid. GC-MS-298, 300 [M+, Br79,81]
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].CCN(C(C)C)C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:25]([Cl:24])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:34])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)ccn(C)c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
To a suspension of 4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt (34 mg, 0.1 mmol) and 2,6-dichlorobenzoyl chloride (25 mg, 0.12 mmol) in dichloromethane (2 mL) was added DIEA (174 μL, 1.0 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 72 h. Then, the mixture was concentrated, the residue was dissolved in ethyl acetate (25 mL), was washed with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (15 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was purified by silica gel chromatography using a Biotage (40 s) column, to afford 23 mg (49% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C24H22Cl2N2O4 (M+Na) 495.0850. found 495.0859. f) Preparation of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][C@@H:14]([OH:16])[CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:18]>O1CCOCC1.O>[OH:16][C@@H:14]([CH3:15])[CH2:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH:1]=[O:18])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cccc(OC[C@H](C)O)c2n1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](O)COc1cccc2ccc(C=O)nc12
Yield: 57 %

Procedure:
To a solution of (S)-1-(2-methylquinolin-8-yloxy)propan-2-ol (0.15 g, 0.69 mmol) in dioxane (10 mL) and water (0.1 mL) was added selenium dioxide (0.092 g, 0.83 mmol) and the resultant mixture heated at reflux for 2.5 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (20-40% ethyl acetate/hexanes) providing the title compound (0.091 g, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=3)[S:17][C:18]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
To a suspension of tert-butyl 4-aminobenzoate (6.36 g, 32.9 mmol) and 2,6-dichlorobenzothiazole (5 g, 24.5 mmol) in isopropanol (150 mL) was added 4 N HCl solution in 1,4-dioxane (1.5 mL, 6 mmol). The mixture was refluxed at 100° C. for 7 h, and then allowed to cool to room temperature. The resulting precipitate was isolated by filtration to yield the first crop of the title compound as a white solid (3.13 g). The mother liquor was concentrated in vacuo and then stirred in a mixed solvent of TFA (20 mL) and dichloromethane (20 mL) overnight. The solvent was removed in vacuo, the obtained residue triturated with isopropanol/ethyl acetate. The isolated white solid was further stirred in a mixed solvent of isopropanol (12 mL) and ethyl acetate (8 mL) for 0.5 h, then isolated by filtration to yield a second crop of the title compound (3.5 g) (total 6.63 g, 85%). HPLC/MS (Method C): retention time=2.51 min, [M+H]+=305.3.
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)CCC.[CH2:38]([N:44]1[CH2:49][CH:48]2[CH:46]([C:47]2([C:51]2[CH:56]=[CH:55][CH:54]=[C:53](I)[CH:52]=2)[CH3:50])[C:45]1=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:38]([N:44]1[CH2:49][CH:48]2[CH:46]([C:47]2([CH3:50])[C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:52]=2)[C:45]1=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cccs2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
To tris(dibenzylideneacetone)dipalladium (0) (4.5 mg, 4.91 lmol) in tetrahydrofuran (1 ml) at room temperature was added triphenylarsine (5.9 mg, 19.2 μmol). After 5 min, 2-(tributylstannyl)thiophene (0.10 g, 0.27 mmol) in tetrahydrofuiran (1 ml) was added followed by 3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 67, 78 mg, 0.19 mmol) in tetrahydrofuran (1 ml). The reaction mixture was stirred at room temperature for 16 h and then refluxed for 2 h. The cooled reaction mixture was concentrated in vacuo and chromatographed on silica gel eluting with hexane:ethyl acetate (2.1) to give the title compound as a colourless oil (68 mg, 98%).
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]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([C@H:27](OS(C)(=O)=O)[CH3:28])(=[O:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C@@H:27]([CH3:28])[C:24]([NH2:25])=[O:26])=[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: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: C[C@@H](OS(C)(=O)=O)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (100 mg, 0.32 mmol), methanesulfonic acid (R)-1-carbamoyl-ethyl ester (64 mg, 0.38 mmol) and potassium carbonate (67 mg, 0.48 mmol) were suspended in DMF (3 mL) and the reaction mixture stirred at RT for 24 h then at 50° C. for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected flash chromatography (SiO2 gradient 0-10% methanol in ethyl acetate) to yield 436 as a white solid (59 mg, 48%). LCMS: RT=3.07 min; [M+H]+=383; 1H NMR (400 MHz, d6-DMSO) 8.26 (1H, d, J=8.6 Hz), 7.81 (1H,$), 7.85 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d, J=2.6 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36 (4H, m), 1.47-1.36 (9H, m). ee>99% (chiralpak IC, 1 mL/min, 20% ethanol in heptane, 50 min run)