Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[CH3:6].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:30]=[N:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=1.[OH-].[NH4+]>C(OCC)(=O)C.ClCCl>[CH3:6][C:5]1[N:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH:30]=[N:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH2:2][CH2:3][N:4]=1
Reactant: COC(=O)c1ccncc1-c1cccc(N)c1
Reactant: CC(=O)NCCCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccncc1-c1cccc(N2CCN=C2C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
N-(2-chloroethyl)acetamide (0.32 g) in ethyl acetate (5 ml) was added over 10 min. to a stirred suspension of phosphorus pentachloride (0.55 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. a solution of methyl 3-(3-aminophenyl)isonicotinate (0.4 g) in dichloromethane (10 ml) was added over 15 min. at 0-5° C. The mixture was stirred at 0° C. for 10 min. and then allowed to warm up to 20° C. After 3 h the mixture was treated with ammonium hydroxide solution (28%, 5 ml) over 10 min. and stirring continued for ca. 1 h. The layers were allowed to separate, the organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:methanol:ammonia=100:10:1, v/v/v) to give 0.25 g (48%) of yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][C:8]=2[F:24])=[N:4][N:3]=1.N1([CH:34]=[O:35])C2C=CC=CC=2N=N1>C1COCC1>[F:24][C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]2=[O:23])[CH:11]=[CH:12][C:7]=1[C:5]1[S:6][C:2]([NH:1][CH:34]=[O:35])=[N:3][N:4]=1
Reactant: O=Cn1nnc2ccccc21
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3nnc(N)s3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3nnc(NC=O)s3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
To a stirred suspension of the compound of Example 30 (184 mg) in dry THF (5 mL) is added 1H-benzotriazole-1-carboxaldehyde (168 mg). The reaction mixture is heated at reflux for 48 hours, cooled and concentrated. The residue is dissolved in EtOH/CH3CN, absorbed onto silica gel and purified by flash chromatography using 7% MeOH in CH2Cl2 as the eluent to yield 155 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)=O.[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[CH2:25][CH2:26][NH2:27].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[CH2:25][CH2:26][NH:27][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cn2)c1
Reactant: NCCC1CC2CCC1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1cccc(-c2ccc(CNCCC3CC4CCC3C4)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-(5-formylpyridin-2-yl)benzamide (Preparation 12, 108 mg, 0.48 mmol) in DCM (75 mL) was added 2-bicyclo[2.2.1]hept-2-ylethylamine (333 mg, 2.39 mmol), AcOH (80 μL, 1.4 mmol) and sodium triacetoxyborohydride (302 mg, 1.42 mmol). The mixture was stirred at rt for 16 h. EtOAc (100 mL) was added and the organic phase washed with aqueous NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (10% MeOH: DCM to 20% MeOH: DCM) to give the title compound: RT=2.62 min; m/z (ES+)=350.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.Cl[C:35](Cl)=[O:36].[NH2:38][NH2:39]>ClCCl>[NH:38]([C:35]([O:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:36])[NH2:39]
Reactant: NN
Reactant: O=C(Cl)Cl
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1OC(=O)NN
Temperature: 0 °C
Yield: 75 %

Procedure:
Dissolve compound 8 (1.0 g, 2.84 mmol) and triethylamine (0.43 g, 4.26 mmol) in dichloromethane (30 ml), add dropwise chloroformyl chloride at 0° C. (0.40 g, 3.98 mmol), after finishing the addition, react at room temperature for 4h, cool the solution to 0° C., add dropwise hydrazine (0.2 g, 5.68 mmol) dichloromethane solution slowly at room temperature, after finishing the addition react at room temperature until finishing the reaction, subsequently wash the solution successively with water, dilute hydrochloric acid and saturated brine, dry the organic layer over anhydrous magnesium sulfate. Filter and concentrate the solution, and redissolve the residue, feed the solution into a chromatographic column, evaporate the solvent in the eluent to obtain a white solid as the target product (0.87 g, 75%). 1H NMR (400 MHz, DMSO-d6): 1.78 (s, 3H), 1.81 (s, 3H), 3.24 (d, J=7.6 Hz, 2H), 3.78 (s, 3H), 3.87 (s, 3H), 45 (s, 2H), 6.73 (s, 1H), 6.79 (d, J=16.0 Hz, 1H), 7.24 (d, J=16.0 Hz, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.6 Hz, 2H), 7.42 (s, 1H), 7.45 (t, J=7.6 Hz, 2H).
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=3)=[N:13][C:12]=2[CH:27]=1)=[O:7])[CH2:3][CH3:4].[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:1].[CH2:2]([N:5]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:25])[NH2:26])=[CH:20][CH:19]=3)=[N:13][C:12]=2[CH:27]=1)=[O:7])[CH2:3][CH3:4]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN(CCC(=O)O)C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1
Yield: 75 %

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 75% of theory, C22H25N5O3S (439.54) Rf value: 0.14 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) ##EQU7##
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][S:8]([CH2:11]P(C1C=CC=CC=1)(C1C=CC=CC=1)=O)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[Si:38]([O:45][C@H:46]1[CH2:50][C@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:48][C@H:47]1[CH:70]=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][S:8](/[CH:11]=[CH:70]/[C@@H:47]1[CH2:48][C@@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:50][C@@H:46]1[O:45][Si:38]([C:41]([CH3:43])([CH3:44])[CH3:42])([CH3:39])[CH3:40])(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1C=O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)CP(=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
tert-Butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate (602 mg, 1.45 mmol) was dissolved in THF (50.0 mL) under an atmosphere of argon, a 1.60 M solution of n-butyllithium in hexane (1.81 mL, 2.89 mmol) was added at −50° C., and the resultant mixture was stirred for 1 h. A solution of (1R,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde (300 mg, 0.60 mmol) in THF (8.0 mL) was added to the mixture, and the resulting mixture was stirred for 30 min at room temperature. After quenching by addition of water (200 mL), the mixture was extracted with EtOAc (100 mL×3). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 10 to 60% EtOAc in hexane to afford the title compound (84.0 mg, 21%). LC/MS: Rt=1.90 min, ES+ 654 (FA standard).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[C:11](Cl)(=[N:13][OH:14])[CH3:12].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:12][C:11]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:14][N:13]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: CC(Cl)=NO
Reactant: c1ccc(Oc2ccccn2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
To a tetrahydrofuran (15 mL) solution of 3-ethynyl-pyridin-2,6-diamine (45 mg, 0.34 mmol) described in Manufacturing Example 13-1-3 and (4-(pyridin-2-yloxy)benzene)-acetohydroximoyl chloride (300 mg, 1.1 mmol) described in Manufacturing Example 209-1-4 was added triethylamine (120 mg, 1.1 mmol), which was stirred for 10 minutes at 60° C. The reaction solution was cooled to room temperature, NH silica gel was added, and the solvent was evaporated under a reduced pressure. The crude product that had adsorbed to the NH silica gel was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1, then ethyl acetate) to obtain the title compound (57 mg, 14%).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[NH2:9][C:10]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>COCCOC>[BrH:1].[Br:16][C:13]1[CH:12]=[N:11][C:10]2[N:15]([CH2:2][C:3]([C:4]([F:7])([F:6])[F:5])([OH:8])[N:9]=2)[CH:14]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Nc1ncc(Br)cn1
Solvent: COCCOC
Product: Br
Product: OC1(C(F)(F)F)CN2C=C(Br)C=NC2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.9 %

Procedure:
A mixture of 1.91 g of 3-bromo-1,1,1-trifluoropropan-2-one and 5 ml of DME was added to a mixture of 1.74 g of 2-amino-5-bromopyrimidine and 15 ml of DME, and the mixture was stirred at room temperature for 1 day. The precipitated solid was taken by filtration, washed with 10 ml of DME, and dried to obtain 1.02 g of 6-bromo-2-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-2-ol hydrobromide.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:15]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CCCCCC>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:22]([N:21]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CCCCCCNCCCCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCN(CCCCCC)S(=O)(=O)c1ccc2nc(C)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A solution of Compound 2 (5.0 g, 20.2 mmol) from step (b) of Example 1 dissolved in chloroform (30 ml) was added drop wise to a solution of dihexylamine (4.5 g, 24.2 mmol) in chloroform (20 ml). The combined mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with water (2×, 50 ml) and brine (1×, 50 ml). The organic layer was then dried with sodium sulfate and evaporated. The residue thus obtained was suspended in ca. 5 ml hot ethyl acetate and this solution was then slowly added to 40 ml hexane. The white solid that precipitated was filtered and the filtrate evaporated to dryness to provide 7.76 g (97%) of Compound 20 as a syrupy liquid, Rf=0.43 (30% ethyl acetate in hexane). The structure of this compound is given below:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]Br)=[C:6]([C:7]([O:9]C)=O)[CH:5]=1.CC[N:20](CC)CC.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH2:32]CN>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:14]([CH2:15][CH2:32][NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)[NH:20][C:7]2=[O:9])=[O:17]
Reactant: NCCNc1ccccn1
Reactant: COC(=O)c1ccc(CCBr)c(C(=O)OC)c1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=O)NC2CCNc1ccccn1
Temperature: 25 °C

Procedure:
A solution of (5) (511 mg, 1.78 mmol) in toluene (10 ml) was treated with Et3N (744 μl, 5.33 mmol) and N1-pyridin-2-yl-ethane-1,2-diamine (244 mg, 1.78 mmol) [prepared by treatment of 2-bromopyridine with excess ethylene diamine and pyridine] and the mixture refluxed for 6 hours. After cooling to room temperature and evaporation of the solvent, the residue was purified by flash chromatography: silica, CH2Cl2/acetone (3:2).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C([N:57]2[CH2:62][CH2:61][C:60]([C:83]3[CH:88]=[CH:87][CH:86]=[C:85](F)[CH:84]=3)([CH2:63][CH2:64][N:65]3[CH:70]4[CH2:71][CH2:72][CH:66]3[CH2:67][CH:68]([N:73]3[C:77]5[CH:78]=[CH:79][CH:80]=[CH:81][C:76]=5[N:75]=[C:74]3[CH3:82])[CH2:69]4)[CH2:59][CH2:58]2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([N:57]2[CH2:58][CH2:59][C:60]([CH2:63][CH2:64][N:65]3[CH:66]4[CH2:72][CH2:71][CH:70]3[CH2:69][CH:68]([N:73]3[C:77]5[CH:78]=[CH:79][CH:80]=[CH:81][C:76]=5[N:75]=[C:74]3[CH3:82])[CH2:67]4)([C:83]3[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH2:61][CH2:62]2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)c2[nH]c(=O)oc12
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(F)c3[nH]c(=O)oc23)CC1
Yield: 17 %

Procedure:
Prepared from a mixture of 4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazole-7-carboxylic acid (9.8 mg, 0.05 mmol, 1 equiv), endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25 mg, 0.05 mmol, 1 equiv), DIEA (36 μL, 0.2 mmol, 4 equiv) and HATU (19 mg, 0.05 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide (example 880). The crude product was purified by prep HPLC (HPLC Method C) to provide 4-fluoro-7-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-1,3-benzoxazol-2(3H)-one as a white solid (5 mg, 17% yield).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([CH3:22])=[N+:16]([O-])[CH:17]=[C:18]([CH3:20])[N:19]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C(Cl)Cl>[Br:3][C:17]1[C:18]([CH3:20])=[N:19][C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])=[C:15]([CH3:22])[N:16]=1.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([CH3:22])=[N:16][CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1c[n+]([O-])c(C)c(-c2ccc(Cl)cc2Cl)n1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: Cc1cnc(C)c(-c2ccc(Cl)cc2Cl)n1
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1Br
Temperature: 25 °C
Yield: 38 %
Yield: 35 %

Procedure:
POBr3 (573 mg) was added to the solution of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine 1-oxide (270 mg) and proton sponge (197 mg) in CH2Cl2 at 0° C. The reaction mixture was warmed to r.t. for 10 h. The reaction mixture was washed with 1N HCl, NaHCO3 and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica gel Heptane:EtOAC 100:1) gave the title compound (110 mg, 35%) and 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine (100 mg, 38%). 1H NMR (CDCl3) δ 2.40, 2.71, 7.28, 7.40, 7.54; MS (ESI+) for C12H9Cl2N2Br1 m/z 333.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:10][C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][C@H:4]1[O:5][CH2:6][CH2:7]2.CC(C)=[O:21].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>O>[C:14]([O:13][C:12]([NH:11][C@@H:9]1[CH2:8][C@H:4]2[O:5][CH2:6][CH2:7][C@@:3]2([C:2]([OH:21])=[O:1])[CH2:10]1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(CO)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product of Step H (426 g, 1.57 mol) and acetone (8.1 L) was added Jones reagent (710 mL) over 1 h 20 min. The resulting suspension was stirred at rt for 1 h, after which isopropyl alcohol (40 mL) was added, and the reaction stirred for 25 min at rt. Water was added, and the water/acetone was decanted off and evaporated. The insoluble material was dissolved separately in water and extracted with CH2Cl2. The green water/acetone concentrate was extracted with CH2Cl2 and the combined organic extracts were washed with brine, diluted with water and EtOAc and the organic layer was dried with Na2SO4. The organic layer was filtered, concentrated and the product was crystallized from MeCN, and the product of Step I was isolated by filtration as a white solid. 1H NMR (400 MHz, DMSO-d6) d=12.39-12.59 (m, 1H), 6.85-7.02 (m, 1H), 4.28 (d, J=5.4 Hz, 1H), 3.89-3.97 (m, 1H), 3.79-3.85 (m, 1H), 3.43-3.51 (m, 1H), 3.30-3.36 (m, 1H), 2.35-2.42 (m, 1H), 1.90 (d, J=11.0 Hz, 3H), 1.59-1.70 (m, 1H), 1.42-1.50 (m, 1H), 1.37 (s, 9H). Elemental anal calc for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C, 57.34; H, 8.18; N, 5.08 mp: 147.4-149.1° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=[O:26])[C:24]#[CH:25]>C1COCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9]([CH:25]=[CH:24][CH:23]=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Reactant: C#CC=O
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1C=CC=O

Procedure:
To a solution of 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (492 mg) in dry THF under nitrogen was added propiolaldehyde (0.97 ml) and the reaction mixture heated to reflux. Further quantities of propiolaldehyde were added in portions (3×1.1 g) during successive 2 h periods. The reaction mixture was concentrated and the deep red residue was purified by FCC eluting with system A (1:4) to give the title product (398 mg) as an off-white solid and as a 1:1 mixture of geometric isomers. δ(CDCl3) 9.48 (d, 1H, J 7.5 Hz, cis CHO), 9.40 (d, 1H, J 7.5 Hz, trans CHO), 7.5 (d, 1H, J 15 Hz, trans CH=CHCHO), 7.45-6.85 (m, 17H, aromatic protons and cis CH=CHCHO), 5.98 (t, 1H, J 7.5 Hz, cis CH=CHCHO), 5.63 (dd, 1H, J 15 and 7.5 Hz, trans CH=CHCHO), 3.25 (septet, 1H, J 7 Hz, CH(CH3)2 of trans isomer), 3.05 (septet, 1H, J 7 Hz, CH(CH3)2 of cis isomer).
Reaction SMILES: [CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4].O.O.Cl[Sn]Cl>C(O)(=O)C>[CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])(=[O:4])=[O:5]
Reactant: COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: COS(=O)(=O)c1ccccc1N

Procedure:
A reaction vessel equipped with a stirrer, a thermometer, and a nitrogen inlet tube was charged with 688 g of 2-nitrobenzene sulfonic acid methyl ester, 4.7 L of acetic acid, and 2.18 kg of SnCl2.2H2O, and the resultant mixture was cooled to 10° C. or less. Hydrochloric acid gas was bubbled through the mixture for 4 hours under stirring. Then, the mixture was stirred for 10 hours at 10° C. or less. Subsequently, 8.4 L of chloroform was added into the reaction mixture, and then while maintaining the temperature at 10° C. or less, the mixture was neutralized with aqueous 20% NaOH. The mixture was separated by further adding 56 L of water. The aqueous phase was extracted with 4 L of chloroform, and then the mixture including the chloroform layer was washed twice with 4 L of water, and separated. The mixture was dried by anhydrous magnesium sulfate, and then filtered to obtain 2-aminobenzene sulfonic acid methyl ester in chloroform solution. The obtained solution was charged along with 950 g of diethylaniline into a reaction vessel equipped with a stirrer, a thermometer, and a nitrogen inlet tube, and then 287 g of acrylic acid chloride was dropped for 15 minutes at a temperature of 5° C. or less. The mixture was stirred for 6 hours while maintaining the temperature at 5° C. or less. Then, 800 ml of concentrated hydrochloric acid and 12.8 L of water were added into the reaction mixture to separate the mixture. The organic layer was washed with, in order, 6.4 L of 2% hydrochloric acid, 6.4 L of water, 6.4 L of aqueous 3% sodium hydrogen carbonate, and 6.4 L of water. The product was dried by anhydrous magnesium sulfate, then filtered, and dried under reduced pressure at 30° C. to obtain 796 g of crystals. These were purified by column chromatography (5 kg silica gel, mobile phase hexane:ethyl acetate=2/1), to obtain 406 g of the monomer 4B represented by Formula (4B).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@@H:33]([CH2:37][OH:38])[C@H:34]([CH3:36])[OH:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:38][CH2:37][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[C@@H:34]([OH:35])[CH3:36]
Reactant: C[C@H](O)[C@@H](N)CO
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 84.2 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.75 g, 3.91 mmol) synthesized in Example (106c) was dissolved in methanol (30 mL), and D-threoninol (1.00 g, 9.51 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.85 g, 10.30 mmol) were added, followed by stirring at room temperature for 5 days under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (1.76 g, yield 84%) as a white solid.