Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10][N:9]1C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])[CH3:3]>CO.[OH-].[OH-].[Pd+2]>[CH3:4][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1NCC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a 100 ml round bottom flask was added (3S)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (1.84 g, 5.25 mmol) in methanol (30 mL), followed by Pd(OH)2 on carbon (20%, wet) (24.7 mg, 0.035 mmol). The mixture was degassed and stirred under an H2 atmosphere (balloon) at room temperature until LCMS indicated completion of the reaction (1 h). The catalyst was filtered off, and the filtrate was concentrated under vacuum to afford (3S)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (1.03 g, 4.77 mmol, 91% yield) as an off white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][CH:40]([OH:52])[CH2:41][N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:38][CH2:39][CH:40]([OH:52])[CH2:41][N:42]2[CH2:51][CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 23.6 %

Procedure:
A solution of 4-acetamidobenzoic acid (100 mg, 0.56 mmol), HATU (234 mg, 0.62 mmol) and TEA (63 mg, 0.62 mmol) in DCM (10 mL) was stirred at 22° C. for 10 min. 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (116 mg, 0.56 mmol) was then added and the solution was stirred at 22° C. for another 3 h. The reaction mixture was then diluted with water and extracted with DCM. The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated and the residue was purified by prep-HPLC to give the title compound (48.5 mg, Yield 24%). 1H NMR (CD3OD, 400 MHz): δ 7.77-7.72 (m, 2H), 7.63-7.57 (m, 2H), 7.17-7.08 (m, 3H), 7.04 (d, J=7.0 Hz, 1H), 4.12 (t, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.58-3.46 (m, 2H), 2.92-2.85 (m, 4H), 2.74-2.63 (m, 2H), 2.16 (s, 3H). LCMS (m/z): 368.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[NH:9][C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])=[CH:7]2.CN(C=O)C.S(Cl)([Cl:40])=O>C1(C)C=CC=CC=1>[Cl:40][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[CH:7]=[C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])[N:9]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (345) (58 g, 130 mmol, 1.0 eq) and DMF (0.5 mL) in toluene (300 mL), sulfurous dichloride (78 g, 0.65 mol, 5.0 eq) was added slowly, and the resulting mixture was stirred at reflux for 2.5 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (5-20% ethyl acetate-petroleum ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate (346).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH2:22][CH3:23])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:22]([C:10]1[N:11]([CH3:21])[C:12]2[C:17]([C:18](=[O:19])[C:9]=1[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)=[CH:16][C:15]([F:20])=[CH:14][CH:13]=2)[CH3:23]
Reactant: CCc1c(-c2cc(F)cc(F)c2)c(=O)c2cc(F)ccc2n1C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1c(-c2cc(F)cc(F)c2)c(=O)c2cc(F)ccc2n1C
Temperature: 25 °C

Procedure:
3-(3,5-Difluorophenyl)-2-ethyl-6-fluoro-1-methylquinolin-4(1H)-one (120 mg, 0.38 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (76 mg, 0.7 eq) were suspended in carbon tetrachloride (5 mL). To the mixture was added benzoyl peroxide (9.2 mg, 0.1 eq) and the mixture was heated at reflux for 3 h. After cooling to rt, satd. aq sodium bicarbonate solution (5 mL) was added. The layers were separated and the aq layer was extracted with DCM (3 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concd under reduced pressure to give 2-(1-bromoethyl)-3-(3,5-difluorophenyl)-6-fluoro-1-methylquinolin-4(1H)-one as a yellow solid. Mass Spectrum (ESI) m/e=397 (M+1). The yellow solid was dissolved in DMF (5 mL) and treated with phthalimide potassium salt (140 mg, 2.0 eq) at 60° C. for 4 h. The reaction mixture was partitioned between water and EtOAc, The layers were separated and the aq layer was extracted with EtOAc (10 mL×2). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by combiflash on silica gel (DCM/hexane, 0/1 to 1/1) to give 2-(1-(3-(3,5-difluorophenyl)-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinolin-2-yl)ethyl)isoindoline-1,3-dione as a white solid. Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].C(O)(=O)C.Cl>O>[NH2:13][C:10]1[C:9]2[C:14](=[O:22])[C:15]([C:17]([OH:19])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]([CH2:4][CH2:5][N:6]3[CH3:23])=[C:2]([F:1])[C:11]=1[F:12]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 71.2 %

Procedure:
20 mg of the compound (201) obtained in Example 72 was added to 0.4 ml of acetic acid and 0.1 ml of 12 N hydrochloric acid, and the solution was heated at 100° C. for 2 hours. After air-cooling, the water was added to the reaction solution, and the deposited solids were filtered off and washed consecutively with water, ethanol and ether to obtain 13 mg of the subject compound (202) in a 72% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:16]2=[CH:17][CH:18]=[N:19][CH:20]=[C:15]2[C:5]2[C:6]([OH:14])=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:14][C:6]1[C:5]2[C:15]3[C:16]([C:2]([CH3:1])([CH3:21])[O:3][C:4]=2[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=1)=[CH:17][CH:18]=[N:19][CH:20]=3)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCCCc1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-n-butyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-n-butyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:20]>CCO>[NH2:20][C:13]1[CH:14]=[CH:15][C:7]2[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:12]=1
Reactant: N
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Solvent: CCO
Product: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Temperature: 100 °C
Yield: 90 %

Procedure:
A solution of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (0.20 g, 0.63 mmol) in EtOH (20 mL) is saturated with ammonia and warmed at 100° C. in a pressure vessel for 30 h. The solvent is removed under reduced pressure to give 7-amino-4-(3-bromoanilino)pyrido[2,3-d]pyrimidine (0.18 g, 90%). 1H NMR (DMSO) δ 9.97 (1H, brs), 8.59 (1H, s), 8.51 (1H, d, J=9.3 Hz), 8.11 (1H, sl brs), 7.77 (1H, brd, J=6.3 Hz), 7.44 (2H, brs), 7.37-7.30 (2H, m), 6.81 (1H, d, J=9.3 Hz).
Reaction SMILES: [N+](=[CH2:3])=[N-].[Br:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl>[Br:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:3])=[O:11])=[CH:8][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1

Procedure:
Diazomethane was added slowly to a suspension of 10 g of 4-(bromomethyl)-benzoic acid in 50 ml of methylene chloride until a persistent yellow coloring of the medium was obtained and excess diazomethane was destroyed by the addition of acetic acid. The mixture was evaporated to dryness and the residue was washed with water and dried under reduced pressure at ambient temperature to obtain 9.25 g of the desired product melting at 54° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH2:15])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20].O.[C:24](Cl)(=[O:26])[CH3:25]>CC(N(C)C)=O>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH:15][C:24](=[O:26])[CH3:25])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20]
Reactant: CNC(=O)CCNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNC(=O)CCNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Yield: 58.8 %

Procedure:
99.5 g. (0.15 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-β -alanine methylamide . 1.1 H2O (IVf), m.p. 250°-252° C. (decomposition) in 190 ml. of dimethylacetamide yield, after reaction with 40.0 ml. of acetyl chloride analogously to Example 1, 60.4 g. (58.8%) of the desired compound. A sample for analysis is purified in alcohol by way of the dimethylammonium salt; m.p. 288°-289° C. (under decomposition).
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].C(O)=O>O>[NH2:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N
Solvent: O=CO
Solvent: O
Product: N#Cc1c(N)sc(C=O)c1Cl
Temperature: 25 °C
Yield: 90 %

Procedure:
48.3 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-formylthien-2-yl)-formamidine in a mixture of 200 parts of formic acid and 200 parts of water are heated at the boil for 3 hours. After the mixture has cooled to room temperature, the product is filtered off under suction, washed with water and dried. 33.5 parts (90% of theory) of 2-amino-4-chloro-3-cyano-5-formylthiophene are obtained. Decomposition temperature: 270° C. (from glacial acetic acid), IR (KBr): 3377, 3298, 3156 (NH2), 2216 (C≡N), 1623 cm-1 (C=0).
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][N:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[N:41]1>ClCCl>[CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:45]([C:42]2[CH:43]=[CH:44][N:40]([CH3:39])[N:41]=2)(=[O:47])=[O:46])[CH2:6][CH2:5]1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CN1CCN(S(=O)(=O)c2ccn(C)n2)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a mixture of 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.1 g, 2.5 mmol) in dichloromethane (20 mL) was added triethylamine (0.52 mL, 3.7 mmol) followed by 1-methyl-1H-pyrazole-3-sulfonyl chloride (0.54 g, 3.0 mmol). The reaction was stirred at RT for 1 h, then quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. After being concentrated to dryness, the residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane to provide the product (1.28 g, 87.7%). LCMS calculated for C26H40N9O3SSi (M+H)+: m/z=586.3; Found: 586.2. The product was separated on a ChiralCel OD-H column (3×25 cm, 5 μM), eluting with a gradient of ethanol in hexanes at flow rate 28 mL/min, to give the two enantiomers. First peak with retention time 20.76 min and second peak with retention time 24.72 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([F:66])=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]3[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@@H:54]([CH3:65])[CH2:53]3)[CH:46]=2)[CH:44]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])(=[O:13])=[O:14])=[CH:7][C:3]=1[C:4]([NH:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([F:66])=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]3[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59])[C@@H:54]([CH3:65])[CH2:53]3)[CH:46]=2)[CH:44]=1)=[O:5]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c(Cl)cc1F

Procedure:
345(b) The 2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorobenzoic acid, was dissolved in 3 mL of DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), and then added in HOBt (1.0 eq, 14.0 mg), and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was then purified using a Gilson to give 1,1-dimethylethyl (2S)-4-[(5′-{[({2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorophenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate.
Reaction SMILES: [ClH:1].[Cl-].[CH3:3][N+:4]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:12])[N:6]([CH3:21])[C:5]=1[S:22][CH2:23][C:24](=[O:26])[CH3:25].[Cl:27]CC(=O)C>CC(C)=O>[ClH:27].[Cl-:1].[CH3:3][NH+:4]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH2:12])[N:6]([CH3:21])[CH:5]1[S:22][CH2:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)CCl
Reactant: CC(=O)CSc1n(C)c(NC(=O)[C@@H](N)Cc2ccccc2)c[n+]1C
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)=O
Product: CC(=O)CSC1N(C)C(NC(=O)[C@@H](N)Cc2ccccc2)=C[NH+]1C
Reaction time: 72 h

Procedure:
1,3-Dimethyl-4-([(L)-phenylalanyl]amino)-2-[(2-oxopropyl)thio]imidazolium chloride hydrochloride was then prepared: To a solution of 0.050 g (0.00128 mol) of the thione above prepared in 12 mL of acetone was added 0.12 g (0.0013 mol) of chloroacetone, and the solution was stirred 3 days. Additional chloroacetone (0.5 mL) was added at this time and the solution was stirred and refluxed for 24 hours. The solution was concentrated under vacuum and the residue was stirred with 5 mL of ethanol saturated with HCl (gas) for 6 hours. The solution was concentrated under vacuum and the residue was crystallized from isopropyl alcohol ether to obtain the desired 1,3-dimethyl-4-([(L)-phenylalanyl]amino)-2-[(2-oxopropyl)thio]-1H-imidazolium chloride hydrochloride; m.p. indeterminate at 90°-100° C. (softens, then foams).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 79%).
Reaction SMILES: [H-].[Na+].[C:3]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])(=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CCCCCC.C1COCC1>[CH2:23]([N:12]([C@@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:22]=[CH2:21]
Reactant: CCCCCCCC(=O)N[C@H](C)c1ccccc1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCN(C(=O)CCCCCCC)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 326 %

Procedure:
Sodium hydride (60%) (0.65 g, 16.3 mmol) was washed with three 20-ml portions of hexane and then suspended in 5 ml of THF. Hereto were added a solution of 2.00 g (8.1 mmol) of (R)-N-octanoyl-1-phenylethylamine in 15 ml of THF, and 1.96 g (16.3 mmol) of allyl bromide, and the reaction was allowed to proceed at room temperature for 1 hour and, then, at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and added dropwise to 20 ml of ice-cooled 1 M hydrochloric acid to thereby terminate the reaction. The resulting mixture was extracted with 30 ml of hexane. The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then distilled off. The desired product was purified on a silica gel column. Thus was obtained 7.59 g (94%) of the title compound.
Reaction SMILES: CC1(C)OC(=O)[CH:5]([CH2:9][C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:4](=O)[O:3]1.CCCCCC>C1(C)C=CC=CC=1>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C@H:10]2[CH2:9][CH2:5][C:4](=[O:3])[N:22]2[C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CC1C(=O)OC(C)(C)OC1=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)cc1

Procedure:
(R)-tert-Butyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (10.0 g, 22.5 mmol) in 100 mL toluene was heated at 105° C. for 3 hours. Hexane was added, and the mixture was sonicated. The resulting solid was filtered. The desired product was obtained as a white amorphous solid (21.0 g, yield 98%). No further purification was performed and the reaction was carried on to the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12].Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: O=C1NCCNC1c1cccs1
Reactant: COC(=O)CCl
Product: COC(=O)CN1CCNC(=O)C1c1cccs1

Procedure:
18.2 g (0.1 mol) of 3-(2-thienyl)-piperazin-2-one, prepared in accordance with Example 16, are reacted with methyl chloroacetate and worked up, as described in Example 6.
Reaction SMILES: [CH:1]([C@@H:3]1[N:6]([C:7](=[O:9])[CH3:8])[C:5](=[O:10])[C@H:4]1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[N:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:2].CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([C@@H:3]1[N:6]([C:7](=[O:9])[CH3:8])[C:5](=[O:10])[C@H:4]1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])=[N:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])([OH:40])=[O:2]
Reactant: CC(C)=O
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Yield: 66 %

Procedure:
To an acetone solution of compound 28 (3.5 g, 6.8 mmol) was added freshly prepared Jones reagent dropwise until TLC indicated the disappearance of the starting material. The acetone layer was separated, and the residue was washed with a fresh portion of acetone. Two acetone portions were combined and concentrated. The residue was purified by silica gel chromatography (EtOAc:MeOH/99:1) to afford 2.4 g (66%) of the title product.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH:33][CH3:34])[CH3:32]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:33]([CH2:31][CH3:32])[CH3:34])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CCNC
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: CCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 13.3 mg (0.23 mmol) of ethylmethylamine are reacted together by general method E. 20.1 mg (36.8% of theory) of the title compound are obtained.