Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.P(Br)(Br)([Br:8])=O.[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N+:20]([O-])=[CH:19][C:18]=1[Cl:26])=[O:16]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N:20]=[C:19]([Br:8])[C:18]=1[Cl:26])=[O:16]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)c[n+]([O-])cc2OC)c(OC)c1OC
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Br)c2Cl)c(OC)c1OC
Yield: 743 %

Procedure:
5 ml of dimethylformamide was added to 2.5 ml of toluene, the mixture was cooled with ice, and 0.7 g (0.2 mmol) of phosphorus oxybromide was dropwise added thereto. After the mixture was stirred under cooling with ice for 10 minutes, 0.42 g (0.1 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine-N-oxide obtained in Synthesis Example 14 (a) was added thereto. After the mixture was stirred under cooling with ice for 30 minutes, the temperature was recovered to room temperature, followed by stirring for 2 hours. 10 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate, subjected to filtration and purified by silica gel column chromatography to obtain 0.32 g (yield 65%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2bromo-3-chloro-5-methoxypyridine (compound No. 245; m.p. 97-99° C.).
Reaction SMILES: [C:1]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([O:12]C)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[OH-].[Li+]>C1COCC1>[C:1]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccn(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.16 g (4.31 mmol) methyl N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate in 16 ml THF are combined with 10 ml of water and 10 ml of 1-molar lithium hydroxide solution are added. After stirring at ambient temperature for 2 h the mixture is evaporated down i. vac., the residue is combined with water, filtered and the filtrate is adjusted to pH 5 with potassium hydrogen sulphate solution. After total evaporation i. vac. the residue is treated with dichloromethane and a little ethanol, suction filtered and the filtrate is evaporated down completely i. vac.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 15.75 h
Yield: 97.2 %

Procedure:
Ethyl difluoroacetate (3.51 g, 28.3 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (6.12 g, 28.3 mmol) followed by 2-acetyl-5-chlorothiophene (4.12 g, 25.6 mmol). A pink precipitate formed after 5 minutes which was dissolved by adding ether (10 mL) and THF (10 mL) to the reaction. The reaction was stirred at room temperature overnight (15.75 hours), then treated with 3N HCl (15 mL). The organic layer was collected and washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a red solid (5.94 g) which was recrystallized from methylene chloride/isooctane to give the diketone as a yellow solid (2.02 g, mp 72°-77° C., 33%). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H) , 7.57 (d, J=4.2 Hz, 1H) , 7.01 (d, J=4.2 Hz, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.01 (d); M+238.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+]>CS(C)=O>[CH2:10]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCBr
Reactant: O=C1CCCN1CCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCCOCCN1CCCC1=O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
1.29 g of 1-(2-hydroxyethyl)-2-pyrrolidone, 4.14 g of n-nonylbromide, 2.24 g of potassium hydroxide in a powder state and 30 ml of dimethyl sulfoxide were mixed together and agitated at room temperature for a whole day. The resulting reaction mixture was extracted with dichloromethane, after which the thus obtained extract was washed with water, dried, feed from the solvent by distillation off and then finally distilled to obtain 2.37 g of colorless 1-[2-(n-nonyloxy) ethyl] azacyclopentane-2-one having the following appearance, column temperature and analysis:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]=O)[CH:2]=[CH2:3].C([N:14]1C=CC=C1C=O)(C)C.C1CCCCC1>ClCCl>[CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:14])[CH:2]=[CH2:3]
Reactant: CC(C)n1cccc1C=O
Reactant: C=CCn1cccc1C=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCn1cccc1C#N
Yield: 50 %

Procedure:
In the same manner as described in Reference Example 2 (1) except that 1-allylpyrrole-2-carbaldehyde (prepared in the same manner as described in Can. J. Chem., 55, 4112, 1977, b.p. 80°-83° C./7 mmHg) (8.1 g, 60 mmole) is used instead of 1-isopropylpyrrole-2-carbaldehyde and further the product is isolated by silica gel column chromatography (solvent, cyclohexane:dichloromethane=3:1) instead of distillation under reduced pressure, there is obtained 1-allylpyrrole-2-carbonitrile (4.0 g, yield: 50%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[C:6]([CH:19]=[O:20])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:4]([C:5]1[C:6]([CH:19]=[O:20])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[C:13]=2[CH:14]=1)#[CH:3]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 7.21 g (23.1 mmol) of 3-(2-trimethylsilyl-ethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde in 150 mL of methanol was added 6.38 g (46.2 mmol) of potassium carbonate. After 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (3% ethyl acetate/hexane) to afford 4.04 g (73%) of 3-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=94.0-94.6° C.).
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:76])([C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH:52]([CH2:58][CH2:59]CCCCC=C)[C:53]([O:55]CC)=[O:54]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:59][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:76])[C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:69])([F:70])[F:71])[C:53]([OH:55])=[O:54])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoic acid.
Reaction SMILES: Cl.[NH2:2][OH:3].O.C([O-])(O)=O.[Na+].[Br:10][C:11]1[C:12]([CH2:17][C:18]#[N:19])=[N:13][CH:14]=[CH:15][CH:16]=1>C(O)C>[Br:10][C:11]1[C:12]([CH2:17][C:18]([NH:2][OH:3])=[NH:19])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: N#CCc1ncccc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Cc1ncccc1Br)NO
Temperature: 25 °C

Procedure:
A vigorously stirred mixture of hydroxylamine hydrochloride (924 mg, 13.3 mmol), water (4 mL), NaHCO3 (1.12 g, 13.3 mmol), 3-bromo-2-cyanomethylpyridine (Intermediate 1) (1.31 g, 6.65 mmol) and ethanol (14 mL) was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, the ethanol was removed in vacuo and the white solid collected by filtration, washing with water (3×10 mL). The wet solid was dried in vacuo at 40° C. for 1 hour to yield 2-(3-Bromo-pyridin-2-yl)-N-hydroxy-acetamidine as a solid (Intermediate 2).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH:44]1([C:50]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)C1CCCCC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:17][O-:18].[Na+]>CN(C)C=O.O>[CH3:17][O:18][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=C1c2ccc(F)cc2OC[C@@H]2CCCN12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OC[C@@H]1CCCN1C2=O
Temperature: 110 °C

Procedure:
A solution of (S)-8-fluoro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]-benzoxazepine-5-one (0.5 g; 2.14 mmol), prepared as described in Example 5A, and sodium methoxide (0.244 g; 4.52 mmol) in dimethylformamide (2 mL) was heated at 110° C. for 3 h. The reaction was diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) to give the title product, m.p. 104-106° C.; EIMS: m/z=234 [M+H]+
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:26][C@@H:27]([CH2:40][NH2:41])[CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1>>[OH:26][C@H:27]([CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[CH2:40][NH:41][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 230) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.85 (t, J=7.0 Hz, 3H), 1.10-1.40 (m, 10H), 1.50-1.70 (m, 4H), 1.95-2.16 (m, 2H), 2.67 (brt, J=11.1 Hz, 2H), 2.93 (brt, J=7.9 Hz, 2H), 2.95-3.20 (m, 3H), 3.62-3.75 (m, 2H), 4.00-4.12 (m, 2H), 4.12-4.30 (m, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 6.80-7.00 (m, 3H), 7.07 (d, J=9.0 Hz, 2H), 9.33 (brs, 1H), 10.60 (brs, 1H), 10.75 (brs, 1H); MS (ES) m/z: 574.1 (MH+); HRMS Calcd. for C29H44N5O5S(MH+): 574.3063. Found: 574.3084.
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)C(CN1CCCC1)NCC2
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2ccc(O)cc21

Procedure:
Prepared as Ex. No. 5, from 3 g (7.61 mmoles) of 1-(pyrrolidin-1-yl)methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 1.9 g (9.31 mmoles) of 3,4-dichlorophenylacetic acid, 2.3 ml (16.36 mmoles) of triethylamine and 3.2 g (15.61 mmoles) of dicyclohexylcarbodiimide in 110 ml of dry chloroform.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH:16]([CH3:20])[C:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: OCc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
Benzyl alcohol (242 mL, 253 g, 2.34 mol) and pyridine (204 mL, 204 g, 2.57 mol) were dissolved in methylene chloride (2.5 L) and cooled to 0° C. 2-Chloropropanoyl chloride (250 mL, 327 g, 2.57 mol) was added dropwise keeping the temperature between 0° C. and 5° C. After addition the mixture was allowed to warm to RT overnight. The mixture was washed with 20% aqueous citric acid (2.5 L), saturated aqueous NaHCO3 (2.5 L), brine (2.5 L), dried (MgSO4), filtered and concentrated in vacuo. The resulting brown liquid (450 g) was dissolved in a small amount of methylene chloride and filtered through a short path of silica gel. After concentration, the crude was purified via bulb-to-bulb distillation (2*10-2 mbar, 90-95° C.) affording the title compound as a pale yellow liquid (420 g, 90%). 1H-NMR: (CDCl3, 300 MHz): δ ppm 1.75 (d, 3H, CH3), 4.45 (q, 1H, CHCl), 5.25 (s, 2H, CH2Ar), 7.40 (m, 5H, ArH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](Br)[CH2:35][CH:36]([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl [(3R,4R)-1-benzyl-4-{[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]carbamate (4.76 g, 10 mmol), isoamyl bromide (1.2 eq), and K2CO3 (2.76 g, 20 mmol) in 50 mL of DMF was stirred overnight at 50° C. The mixture was diluted with H2O, extracted with EtOAc, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5→20% EtOAc in hexane to give the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][OH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C>CO>[CH3:16][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:14][OH:15]
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(CCO)NC(=O)OC(C)(C)C

Procedure:
2-tert-Butoxycarbonylamino-4-hydroxy-butyric acid (0.79 g, 3.6 mmol) was dissolved in 15 ml methanol at room temperature and (trimethylsilyl)diazomethane (2M solution in hexane) was added till solution become yellow. The mixture was concentrated down to afford crude 2-tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Br:31][C:32]1[N:33]=[CH:34][C:35]([C:19]2[CH:18]=[N:17][C:16]([C:8]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[CH:36][CH:37]=1
Reactant: Brc1ccc(I)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)cn1
Temperature: 80 °C
Yield: 61 %

Procedure:
A mixture of 1-phenyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H-benzo[d]imidazole (3 mmol), 2-bromo-5-iodopyridine (1.98 g, 7 mmol) (Compound 10), Pd(PPh3)4 (0.346 g, 0.3 mmol) and potassium carbonate (0.828 g, 6 mmol) in dioxane/water (50 mL/10 mL) was degassed and heated at about 80° C. overnight. The mixture was poured into ethyl acetate (250 mL), washed with water, then brine, dried over Na2SO4, loaded on silica gel and purified by flash column (hexanes/dichloromethane 1:1 to dichloromethane to dichloromethane/ethyl acetate 9:1 to 4:1). The desired fraction was collected and concentrated, then filtered to give a light yellow solid (Compound 11) (0.78 g, in 61% yield).
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]2)[C:17]([F:28])=[CH:16][N:15]=1>C1COCC1.[Zn]>[Cl:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C@:23]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([OH:27])[CH2:22]2)[C:17]([F:28])=[CH:16][N:15]=1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N2. THF (8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at room temperature then heated to reflux and cooled. A solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture, then a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCO3 solution were added and the product was extracted with additional EtOAc (3×), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes:EtOAc) separated 2 products. Fractions containing the second (minor) peak were combined and concentrated to give 470 mg of 63a. LCMS+: 332.13 at 3.2 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[S:7][CH:6]=[C:5]([OH:8])[CH:4]=1.Cl[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[N:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:17]1([N:16]2[C:12]([O:8][C:5]3[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[S:7][CH:6]=3)=[N:13][N:14]=[N:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: Oc1csc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cc(Oc2nnnn2-c2ccccc2)cs1
Yield: 67.3 %

Procedure:
A solution of 5-trifluoromethyl-thiophen-3-ol (2.0 g, 11.9 mmol) in dry acetone (480 mL) containing 5-chloro-1-phenyl-1H-tetrazole (2.1 g, 11.9 mmol) and K2CO3 (3.3 g, 23.8 mmol) is maintained at reflux with careful exclusion of moisture overnight. The acetone is removed under reduced pressure and the residue is partitioned between CH2Cl2 (500 mL) and H2O (50 mL). The organic extracts are washed with brine, then dried (Na2SO4), filtered and concentrated. The crude product is chromatographed on silica gel, eluting with EtOAc:Hex (1:80) to afford the title compound (2.5 g, 68%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)#[N:2].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)(=[O:22])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(C#N)nc1-2
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OCCn1cc(C(N)=O)nc1-2
Yield: 75.8 %

Procedure:
Methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.46 g, 1.7 mmol) was stirred with potassium carbonate (469 mg, 3.4 mmol), water (1.2 mL) and hydrogen peroxide (408 mg, 6 mmol) in DMSO (7 mL) for 4 hours. The mixture was diluted with 70 mL of water and extracted with ethyl acetate. Ethyl acetate solution was washed with water, 5% Na2S2O3, water, brine, dried over MgSO4 and concentrated under vacuum to give methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.37 g).