Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=O)([O-:3])=[O:2].[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)COc1ccccc1[N+](=O)[O-]
Reactant: Cc1cccc(N)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)COc2ccccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Nitrophenoxy)acetic acid S11 (5.28 g) and 2,3-dimethylaniline (3.25 g) were dissolved in dichloromethane (100 ml). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.17g) and 4-dimethylaminopyridine (3.93 g) were added to the solution, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed successively with 1N HCl saturated aqueous sodium hydrogencarbonate solution and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, obtaining 7.7 g of the compound S12.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([F:22])([F:21])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[OH:24][CH:25]1[CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][CH2:28][N:27]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:26]1>>[F:21][C:12]([F:22])([CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]2[CH2:29][CH2:28][N:27]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:26][CH:25]2[OH:24])=[CH:36][CH:35]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)COc2ccccc2)cc1
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(OCC(F)(F)COc3ccccc3)cc2)C(O)C1

Procedure:
Analogously to Method G, 0.350 g of 2,2-difluoro-3-phenoxypropyl toluene-4-sulphonate and 0.452 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate are reacted. The title compound is obtained as a yellow oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=5.11.
Reaction SMILES: [CH:1]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Cl)[N:7]=1)([CH2:3][CH3:4])[CH3:2].C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[CH:1]([S:5][C:6]1[N:7]=[C:8]([CH2:12][O:27][C:23]2[C:22]([F:28])=[CH:21][C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])=[CH:25][C:24]=2[F:26])[CH:9]=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CCC(C)Sc1cccc(COc2c(F)cc(CCC(=O)O)cc2F)n1
Yield: 65 %

Procedure:
2-sec-Butylsulfanyl-6-chloromethyl-pyridine (0.06 g, 0.27 mmol) obtained in Step C of Preparation Example 5 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A Example 1 to obtain the title compound (0.074 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31]O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:52]([NH2:63])(=[O:62])[C:53]1[C:54](=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:55](N)=[O:56]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][N:63]2[C:52](=[O:62])[C:53]3[C:54](=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:55]2=[O:56])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1ccccc1C(N)=O
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc3c(c2)c(NCCN2C(=O)c4ccccc4C2=O)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
To a stirred solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (0.6 g), from Synthetic Example 22, in THF (14.3 mL), under Argon, was added sequentially triphenylphosphine (1.08 g, 4.13 mmol), phthalamide (0.21 g, 1.45 mmol), followed by diisopropyl azadicarboxylate (DIAD, 0.31 g, 1.52 mmol) dropwise over 30 minutes. The mixture was stirred overnight at room temperature. The mixture was quenched with saturated sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried and concentrated. The residue was partially purified by chromatography on silica gel, followed by preparative reverse phase HPLC to give 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester (131 mg) which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([C:8](=O)[CH3:9])[C:6]#[N:7].O.[NH2:16][NH2:17]>C(O)C>[CH3:9][C:8]1[C:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[CH3:1])=[C:6]([NH2:7])[NH:17][N:16]=1
Reactant: CC(=O)C(C#N)Cc1ccccc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccccc1Cc1c(C)n[nH]c1N
Temperature: 25 °C
Yield: 37.8 %

Procedure:
To a solution of 2-(2-methylbenzyl)-3-oxobutanenitrile (7.39 g, 39.5 mmol) in ethanol (400 mL) was added hydrazine hydrate (1.97 g, 39.5 mmol) and stirred under reflux for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1 then DCM:methanol=40:1) to provide the titled compound (3.005 g, 38%) as a yellow solid; LC/MS: MS (ES+) m/e 202 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.12 (s, 3H), 2.33 (s, 3H), 3.63 (s, 2H), 7.07-7.17 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:17]([O:16][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[S:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=1)=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[F:13])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Reactant: FC(F)(F)c1cccc(S)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Sc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
The reaction mixture of 100.0 mg (0.37 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline, 80.3 mg (0.44 mmol) of 3-trifluoromethylthiophenol and 80 μL of diisopropylethylamine in 2.0 mL of N,N-dimethylformamide was stirred at room temperature for 2 h and cooled. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and concentrated. The resulting residue was purified on silica gel column eluting with ethyl acetate-hexane (1:3) to give 30.0 mg (20%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.O[C:23]1C=CC(C#N)=C(C)C=1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:17]([CH3:23])[CH:18]=2)[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: Cc1cc(O)ccc1C#N
Product: Cc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (0.65 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-2-methyl-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.62 min, [M+H]+=281.0.
Reaction SMILES: CC(OC([NH:8][C@@H:9]1[C:12](=[O:13])[O:11][CH2:10]1)=O)(C)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(O)(C(F)(F)F)=O>[C:14]1([CH3:24])[CH:15]=[CH:16][C:17]([S:20]([OH:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[NH2:8][C@H:9]1[CH2:10][O:11][C:12]1=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1COC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COC1=O

Procedure:
BOC-L-serine β-lactone (600. mg, 3.20 mmol) and anhydrous p-toluenesulfonic acid (579 mg, 3.36 mmol) were treated with distilled CF3COOH (10 mL) at 0°-5° C. for 10 min. Removal of solvent in vacuo as above provided a white crystalline residue which was triturated with dry Et2O (20 mL) and filtered to yield (S)-3-amino-2oxetanone p-toluene sulfonic acid salt (806 mg, 97%). This material was analytically pure; however, if desired, recrystallization could be effected from DMF/Et2O (25° C.→-20° C.): mp (~4° C./min) 135° C. (darkening), 173° C. (dec. rapid); [α]D25 -15.9 (±0.1)° (c 2.2, DMF); IR 3040 (s, vbr), 1838 (vs), 1600 (w), 1585 (w), 1550 (m) cm-1 ; IR (pH 6.8, aqueous solution) 1820 cm-1 ; IR (DMF solution) 1830 cm-1 ; 1H NMR (300 MHz, d7 -DMF)δ 7.66 (d, 2H, 8.0 Hz, o-ArH), 7.15 (d, 2H, 8.0 Hz, m-ArH), 5.53 (dd, 1H, 4.6, 6.5 Hz, CH), 4.74 (m, 1H, CHHO), 4.68 (m, 1H, CHHO), 3.70 (vbr s, 3H, NH3 +), 2.31 (s, 3H, ArCH3); 13C NMR (75.5 MHz, d7-DMF) δ 165.84, 145.12, 139.14, 128.67, 126.08, 64.70, 57.45, 20.70. Anal. Calc. for C10H13NO5S: C, 46.32; H, 5.05; N, 5.04; S, 12.37. Found: C, 46.44; H, 5.14; N, 5.24; S, 12.41; POSFAB-MS (glycerol) 88 (MH+ =C3H6NO2), 180 (MH+ (gly)), 260 (MH+ (TsOH)). The enantiomeric (R)- 3-amino-2-oxetanone salt was produced in an identical manner from BOC-D-serine β-lactone prepared from BOC-D-serine.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].[CH2:15](I)[CH2:16][CH3:17].O>CN(C=O)C>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:15][CH2:16][CH3:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCI
Reactant: CCN(CCO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCN(CC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(N-ethylanilino)ethanol (17.83 g) in DMF (300 ml) was added at 0° C. sodium hydride (60%, 4.74 g), and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. To the mixture was added propyl iodide (11.0 ml), and the mixture was stirred at 50° C. for 19 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:19) to give colorless oil of N-ethyl-N-(2-propoxyethyl)aniline (10.18 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Temperature: 25 °C

Procedure:
4-carboxyphthalic anhydride (benzene tricarboxylic acid anhydride) (1.0 g, 0.0052 mol), glycine (0.3907 g, 0.0052 mol) and 50-60 mls of glacial acetic acid were added to a 100 ml round-bottom flask equipped with a reflux condenser, heating mantle and stir plate. The system was placed under a N2 atmosphere and heated to a gentle reflux. The progress of the reaction was monitored by TLC. After 7 hours the clear colourless solution was cooled to room temperature. The resulting white precipitate was filtered through a Buchner funnel and washed three times with 10 mls of distilled water. This crude material was recrystallized in EtOH/H2O to afford the desired product as a powdery white solid. The filtrate was evaporated under vacuum using a rotary evaporator. The crude material was recrystallized from EtOH/H2O to yield a second batch of white powdery product. Individual batches were dried in air for 24 hours and then in vacuo for 48-72 hours to afford 100 in a combined yield of 1.02 g (78%): mp=262-265° C.; Rf0.70 (A): Rf0.47 (B): Rf0.20 (D): 1H NMR (DMSO-d6) δ4.33 (s, 2H), 8.02 (d, J=7.8 Hz, 1H), 8.24 (bs, 1H), 8.36 (d, J=7.8 Hz, 1H); MS m/z (rel intensity) 249 (13), 248 (100), 204 (36); IR (cm−1): 2750-3300 (OH), 3052 (C═CH), 2671 (C—H), 1776 (C═O), 1731 (C═O), 1705 (C═O), 1620 (C═C), 1420 (C═C), 1300 (C—O), 1122 (C—O), 746 (C═CH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][N:34]3C(=O)C4=CC=CC=C4C3=O)[CH:27]=2)[C:10]1=[O:45].O.NN>C(O)C>[NH2:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([N:11]2[C:12]3=[N:13][C:14]([NH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:15][CH:16]=[C:17]3[CH2:18][N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:10]2=[O:45])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 47.5 %

Procedure:
A solution of 30 mg (0.05 mmol) of 3-(2,6-dichlorophenyl)-7-anilino-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 5 ml of ethanol was treated with 0.02 ml of hydrazine hydrate. After 5 hours the mixture was evaporated and 10 ml of dichloromethane were added to the residue. The resulting suspension was filtered and the filtrate was evaporated. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 12 mg (50%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2,6-dichlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 208° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:28][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:28][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Yield: 82.9 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (0.74 g, 2.0 mmol), tert-butyl azetidin-3-ylcarbamate (0.35 g, 2.0 mmol) and DMAP (0.75 g, 6.1 mmol) in MeCN (60 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.84 g (83%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.32 (s, 9 H), 1.49-1.64 (m, 4 H), 1.66 (s, 9 H), 2.29-2.45 (m, 1 H), 3.30-3.41 (m, 2 H), 3.63 (m, 2 H), 3.88-4.01 (m, 4 H), 4.03-4.14 (m, 1 H), 4.52 (d, J=7.62 Hz, 2 H), 7.90 (dd, J=8.59, 1.37 Hz, 1 H), 8.05 (d, J=8.79 Hz, 1 H), 8.15 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=506.8; Anal. Calcd for C25H38N4O5S+0.90 TFA+0.10 EtOAc+0.50H2O (628.31): C, 52.19; H, 6.53; N, 8.92. Found: C, 52.13; H, 6.53; N, 8.84.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([O:48][CH:49]([CH3:51])[CH3:50])[C:42]([F:47])=[C:43]([CH:46]=1)[CH:44]=[O:45])[CH3:37]>C1COCC1>[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([O:48][CH:49]([CH3:50])[CH3:51])[C:42]([F:47])=[C:43]([CH:44]([C:9]2[N:10]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[OH:45])[CH:46]=1)[CH3:37]
Reactant: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CCOc1cc(C=O)c(F)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(OC(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 75.8 %

Procedure:
To a solution of Intermediate 8.1 (200 mg, 0.517 mmol) in 3 mL THF at 0° C., was added BuLi (1.4 M in THF, 0.406 mL, 0.569 mmol). The mixture was stirred at 0° C. for 25 min, then a solution of Intermediate 7.2 (117 mg, 0.517 mmol) in 1 mL THF was added dropwise. The mixture was stirred at 0° C. for 30 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 240 mg of Intermediate 25.1 as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].O.[OH-].[Na+].[CH3:15][C:16]([CH3:18])=[O:17]>>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:15]/[C:16](=[O:17])[CH3:18])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Yield: 78 %

Procedure:
The mixture of 3-nitrobenzaldehyde (15.1 g, 0.1 mol), acetone (20 mL) and water (40 mL) was slowly added 5% aqueous NaOH (8 mL) from a dropping funnel at 40° C. After the reactant disappeared in TLC monitoring, acetone was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated to give the (E)-4-(3-nitrophenyl)but-3-en-2-one (15 g, 78% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ 8.31 (t, 1H), 8.15 (t, 1H), 7.83 (d, 1H), 7.52 (t, 1H), 7.44 (d, 1H), 6.70 (d, 1H), 2.33 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[NH:10])OCC)=[CH:4][CH:3]=1.[CH3:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH2:19][S:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:13][C:14]1[NH:15][CH:16]=[N:17][C:18]=1[CH2:19][S:20][CH2:21][CH2:22][NH:23][C:6](=[NH:10])[C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:12][CH:11]=1
Reactant: CCOC(=N)c1ccc(S)cc1
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=N)c1ccc(S)cc1

Procedure:
4-Cyanothiophenol was treated with hydrogen chloride in ether at 0° and the hydrochloride salt produced was treated with potassium carbonate to give ethyl 4-mercaptobenzimidate. Ethyl 4-mercaptobenzimidate was treated with 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole in dry ethanol at room temperature to give the title product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[NH:3][CH2:2]1.[N:10]([O-])=[O:11].[Na+]>Cl>[N:10]([N:3]1[CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6][O:1][CH2:2]1)=[O:11]
Reactant: O=N[O-]
Reactant: O=C(O)C1CCOCN1
Agent: Cl
Agent: [Na+]
Product: O=NN1COCCC1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tetrahydro-2H-1,3-oxazine-4-carboxylic acid (i.e. the product of Step A) (2.00 g, 15.3 mmol) was dissolved in 1 N hydrochloric acid (12.4 mL), and the solution was cooled to 0° C. Sodium nitrite (1.42 g, 20.6 mmol) was then added portionwise, and the reaction mixture was stirred for 1 h. The reaction mixture was then extracted twice with dichloromethane and once with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.29 g of the title compound as a solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([NH2:30])(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1>[C:15](=[S:2])([NH2:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCC(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(N)=S
Yield: 191.5 %

Procedure:
Phosphorus pentasulfide (9.8 g, 0. 044 mol) was added to a mixture of tetradecanamide (8.6 g, 0.04 mol) in dry THF (250 mL) and the mixture refluxed overnight, concentrated in vacuo, and heated with methanol (200 mL), filtered, and the filtrate concentrated in vacuo to yield a pale yellow solid (10.28 g, 99%) used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1CCNCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(N)CC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.08 (m, 1 H), 7.84-7.71 (m, 3 H), 7.62-7.59 (m, 3 H), 6.50 (s, 1 H), 5.34 (s, 2 H), 4.57-4.55 (m, 2 H), 3.96-3.86 (m, 2 H), 3.78-3.76 (m, 2 H), 3.48-3.45 (m, 1 H), 3.13-3.08 (m, 2 H), 2.48 (s, 3 H), 2.27-2.23 (m, 2 H), 2.02-1.92 (m, 2 H).