Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([C@@H:41]([CH2:45]O)[C:42]([OH:44])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:47]([OH:50])(=[S:49])[CH3:48]>O1CCCC1>[C:47]([S:49][CH2:45][C@H:41]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:42]([OH:44])=[O:43])(=[O:50])[CH3:48]
Reactant: O=C(O)[C@H](CO)Cc1ccccc1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC[C@H](Cc1ccccc1)C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2.44 g (12.05 mmol) of diisopropyl azodicarboxylate are added dropwise, at 0° C., to a solution of 3.16 g (12.05 mmol) of triphenylphosphine in 30 ml of tetrahydrofuran. Once the addition is complete, the mixture is stirred for 30 minutes at this temperature. The reaction medium is cooled to -10° C. and a solution of 1.45 g (8.05 mmol) of (S)-2-benzyl-3-hydroxypropionic acid (X S) and 0.92 g (12.05 mmol) of thioacetic acid in 10 ml of tetrahydrofuran is added dropwise. Once the addition is complete, the mixture is stirred for one hour at -10° C. and for a further two hours at room temperature.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CCOCC.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[C:17]1([S:23]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: On1nnc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccccc1
Yield: 73 %

Procedure:
In 1 N aqueous sodium hydroxide (50 ml) is dissolved 1-hydroxy-6-chloro-1,2,3-benzotriazole (4.5 g) and thereto is added ether (10 ml). To the solution is added benzenesulfonyl chloride (6.0 g) with stirring under ice-cooling and the mixture is stirred at the same temperature for 75 minutes. The reaction mixture is filtered to give crystals. The filtrate is extracted with ethyl acetate (150 ml), and the extract is distilled to remove the solvent. The resulting crystals are combined with those obtained above and recrystallized from benzene-n-hexane to give 1-benzenesulfonyloxy-6-chloro-1,2,3-benzotriazole (6.0 g), melting point: 110°-110.5° C. Infrared spectrum (Nujor): 1200, 1086 cm-1.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][NH:8][C:9]2[CH:21]=[C:20]3[C:12]([C:13]4[C:14]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([N:31]6[CH2:39][C:38]7[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=7)[C:32]6=[O:40])[C:26]=5[CH3:41])=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=[O:23])[C:18]=4[NH:19]3)=[CH:11][CH:10]=2)[CH2:4][O:3]1.Cl.[OH-].[Na+]>C1COCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[C:14]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH2:39][C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[C:32]5=[O:40])[C:26]=4[CH3:41])=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=[O:23])[C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(NC[C@H]5COC(C)(C)O5)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(NCC(O)CO)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A solution of 7-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methylamino)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 66-15, 50 mg, 0.089 mmol) in THF (1 mL) was treated with 2 M hydrochloric acid (4.46 mL, 8.92 mmol) and the mixture was stirred at rt for 1 h. The mixture was made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases, along with some insoluble precipitate, were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 7-(2,3-dihydroxypropylamino)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an orange solid (20 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 7.90 (1H, d, J=7.49 Hz), 7.79 (1H, d, J=7.77 Hz), 7.67-7.74 (2H, m), 7.58-7.62 (1H, m), 7.49-7.55 (2H, m), 7.42 (1H, dd, J=6.94, 1.94 Hz), 6.99 (1H, d, J=7.77 Hz), 6.86 (1H, d, J=8.32 Hz), 6.81 (1H, d, J=1.94 Hz), 6.45 (1H, dd, J=8.74, 1.80 Hz), 4.97 (2H, s), 3.88-3.93 (1H, m), 3.59-3.68 (2H, m), 3.36-3.39 (1H, m), 3.14-3.20 (1H, m), 1.95 (3H, s). Mass spectrum m/z 521.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:14])[C:5]=2[S:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c(Br)csc12
Product: Clc1ncnc2c(Br)csc12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
7-Bromothieno[3,2-d]pyrimidine-4(3H)-one (5.9 g) was dissolved in POCl3 (20 mL) and then stirred at 150° C. for 3 hours. After cooling down to room temperature, the remaining POCl3 was concentrated and added to ice water to obtain a solid. The solid was washed with sat. NaHCO3 solution and dried with N2 gas to obtain the title compound.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13](C2N=CNN=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1)(=O)C.[CH3:27][O:28][CH2:29][CH2:30][OH:31]>>[NH2:4][C:5]1[N:14]=[C:13]([O:31][CH2:30][CH2:29][O:28][CH3:27])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1
Reactant: COCCO
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(-c3ccc(F)cc3)ccc2n1
Product: COCCOc1nc(N)nc2ccc(-c3ccc(F)cc3)cc12
Yield: 84 %

Procedure:
This compound, synthesized from 2-acetamido-6-(4-fluorophenyl)-4-(1,2,4-triazolyl)-quinazoline and 2-methoxyethanol in 84% yield using the same procedure as in example 18, was characterized by its mass spectrum as follows: MS (m/z): 299 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2Br)[CH:12]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].CN(C)CC(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH:12]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]([OH:33])=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)COc1ccc(F)cc1C1c2cccc(Br)c2CCN1C(=O)OCc1ccccc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc2c1CCN(C(=O)OCc1ccccc1)C2c1cc(F)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture under Ar of (±)-5-bromo-1-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (108 mg, 0.20 mmol, 1.00 eq.), methanesulfonamide (23 mg, 0.24 mmol, 1.20 eq.), N,N-dimethylglycine (4.3 mg, 0.04 mmol, 0.2 eq.), potassium phosphate tribasic (106 mg, 0.50 mmol, 2.5 eq.), and copper (I) iodide (7.6 mg, 0.04 mmol, 0.2 eq.) in DMF (2 mL) was stirred at 150° C. for 48 hours. The mixture was allowed to cool to r.t. and partitioned between AcOEt (25 mL) and H2O (25 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (1.0 mL). 1M aq. NaOH soln. (1.0 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with 1M aq. HCl soln. (1.0 mL), then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 uM, acidic conditions, detection: UV/MS) to give the desired acid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][N:11]([C:21]2[C:22]([Cl:37])=[C:23]([NH:29]C(=O)OC(C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[CH:26]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:29][C:23]1[CH:24]=[C:25]([CH:26]=[C:21]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10]2)[C:22]=1[Cl:37])[C:27]#[N:28]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CC[C@@H](N3CCOCC3)[C@H](O[Si](C)(C)C(C)(C)C)C2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1N1CCOCC1
Yield: 94 %

Procedure:
(+/−)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (138 mg, 0.250 mmol) was treated with TFA (25% in 1,2-dichloroethane, 3 mL, 9.73 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-40% ethyl acetate/hexanes). (+/−)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-4-chlorobenzonitrile (106 mg) was obtained as a yellow/brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:8])[NH:6][CH:7]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c[nH]c(=O)c(-c2ccccc2)c1
Reactant: Ic1ccccc1
Product: Cc1cc(-c2ccccc2)c(=O)n(-c2ccccc2)c1
Yield: 77 %

Procedure:
5-Methyl-3-phenyl-2-(1H)-pyridone (B. E. Witzel, et al. Brit. Patent 1,238,959) is reacted with iodobenzene as in Example 1 to give 1,3-Diphenyl-5-methyl-2-(1H)-pyridone in 77% yield.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14]C(=O)OC(C)(C)C)=[N:12][CH:13]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CC[C@H](F)C2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CN2CC[C@H](F)C2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
To a solution of (S)-tert-butyl 5-((3-fluoropyrrolidin-1-yl)methyl)pyridin-2-ylcarbamate 119 (7.00 g, 23.7 mmol) in dichloromethane (70 mL) was added TFA (15.5 g, 142 mmol). The mixture was stirred for 12 h at room temperature. The solvent was removed in vacuo and sat. aq Na2CO3 was added. The mixture was extracted with dichloromethane, dried (MgSO4) and concentrated to give 120 (4.50 g, 97% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCOc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (63%); off white powder, mp 235° C.; MS: 420.5 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([OH:29])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:33]2)=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>N1C=CC=CC=1.C(OCC)(=O)C.N1(C2C=CN=CC=2)CCCC1>[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([O:29][C:5](=[O:6])[CH:4]([CH2:8][CH2:9][CH3:10])[CH2:1][CH2:2][CH3:3])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:33]2)=[CH:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCC(CCC)C(=O)Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC(CCC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
15 mg (0.1 mmol) of 4-(1-pyrrolidinyl)pyridine and 592 mg (3.6 mmol) of 2-propylvaleryl chloride were added to a solution of 1.0 g (1.8 mmol) of (4R,6R)-6-{2[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}-tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] in 5 ml of dry pyridine, whilst ice-cooling, and the resulting mixture was stirred at 70° C. for 3 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate, and the diluted mixture was then washed with 100 ml of water, 100 ml of a 10% w/v aqueous solution of hydrogen chloride, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous magnesium sulfate, after which this layer was removed by filtration. The resulting filtrate was concentrated by evaporation under reduced pressure and the residue obtained was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture hexane and ethyl acetate as the eluent, to give 1.15 g (93% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](Cl)=[N:21][OH:22])=[CH:18][C:17]=1[CH3:26].C(=O)([O-])O.[K+]>O1CCCC1>[Br:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:11]([F:14])([F:12])[F:13])[O:22][N:21]=2)=[CH:18][C:17]=1[CH3:26]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C(Cl)=NO)ccc1Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In a solution of 22.7 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene produced in Step 1 of Synthetic Example 3 and 26.0 g of 4-bromo-α-chloro-3-methylbenzaldoxime in 120 ml of tetrahydrofuran, 15.7 g of potassium hydrogen carbonate was added, and stirred under reflux with heat for 5 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, then the solvent was distilled off under reduced pressure. 150 ml of water was added in the residue, stirred at room temperature for 18 hours, and precipitated crystal was filtered off and dried to obtain 38.6 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[C:15]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[S:14][C:13]=12)=[O:8]
Reactant: Cc1ncsc1C(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3scnc3C)c2s1

Procedure:
The title compound (254 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 502 mg of 7-(4-methylthiazol-5-yl)carbonylimidazo[5,1-b]thiazole, 0.598 ml of tri-n-butylstannyl chloride, and 4.0 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:38]([C:39]#[N:40])=[C:37]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[N:36]=[C:35]([S:46][CH2:47][C:48]3[N:49]=[C:50]([C:53]4[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=4)[S:51][CH:52]=3)[C:34]=2[C:60]#[N:61])=[CH:29][CH:28]=1)=[O:22])[CH3:20])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.[ClH:62]>ClCCl.C(OCC)C>[ClH:59].[ClH:62].[NH2:8][C@H:9]([C:16]([NH:18][C@H:19]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:38]([C:39]#[N:40])=[C:37]([N:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)[N:36]=[C:35]([S:46][CH2:47][C:48]3[N:49]=[C:50]([C:53]4[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=4)[S:51][CH:52]=3)[C:34]=2[C:60]#[N:61])=[CH:31][CH:32]=1)=[O:22])[CH3:20])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
169 mg (0.192 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-histidyl-L-alaninate were dissolved in 3 ml dichloromethane, and 1.915 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, the precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 75 mg (44% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[CH:11][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: Cc1cccc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Temperature: 25 °C
Yield: 84.7 %

Procedure:
20 g (92.5 mmol) of 2-ethoxymethylene-malonic acid diethyl ester and 10 g (92.5 mmol) of 2-amino-6-methylpyridine were heated neat at 110° C. for 2 h. The reaction was allowed to cool to room temperature and the product was recrystallized from dichloromethane and hexane to afford 21.8 g of 2-[(6-Methyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[C:1]([O:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: OC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CCCC1
Reaction time: 8 h

Procedure:
Acryloyl chloride (75 mL) was added to a stirred solution of cyclopentanol (88 g, 1 mol) and triethylamine (175 mL) in dry THF (500 mL) at a rate slow enough to prevent overheating of the reaction. The reaction mixture was allowed to stand overnight, filtered through a pad of Celite, evaporated to an oil, and distilled to give cyclopentyl acrylate as a colorless liquid (bp 74-79/˜60 mm Hg). The structure of the product was confirmed by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:23]1[C:31]2[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[CH:13]1C(=O)O[C:16](C)([CH3:20])[O:15][C:14]1=[O:22]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]([C:23]1[C:31]2[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[CH2:13][C:14]([O:15][CH2:16][CH3:20])=[O:22]
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1Cl)c1c[nH]c2c(CSC)cccc12

Procedure:
2.8 mg (45 μmol) of copper powder were added to a solution of 3.64 g (approx. 5.12 mmol, 72% purity) of the compound from Example 93A in 41 ml of pyridine and 10 ml of ethanol. The reaction mixture was heated under reflux overnight. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 1.34 g (57% of theory) of the title compound.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[CH3:6][C:7]1[C:15]([CH3:17])([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[OH-].[Na+].CO>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:6])[C:15]2([CH3:17])[CH3:16])([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC1=Nc2ccccc2C1(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=Nc2ccc([N+](=O)[O-])cc2C1(C)C
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
Sodium nitrate (3.84 g, 45.2 mmol) was dissolved in concentrated sulphuric acid (100 ml). After cooling in ice, this solution was added to a solution of 2,3,3-trimethylindole (6.65 g, 41 .8 mmol) in concentrated sulphuric acid (100 ml) such that the temperature was maintained in the range 0-5° C. The reaction was stirred at 0-5° C. for 90 minutes after completing the addition, then allowed to warm to room temperature and stirred for a further 16 hours. The mixture was poured onto ice (200 g) then made basic by the addition of 50% aqueous sodium hydroxide solution to pH12 (pH paper). The crude product was collected by filtration and washed with water until the washings were neutral (˜1000 ml). The off-yellow solid was dried at the pump, dissolved in ethyl acetate (250 ml) and dried further (MgSO4). The solution was filtered and the red filtrate was rotary evaporated to dryness. The solid was dissolved in chloroform:ethyl acetate (95:5, 30 ml) and purified by silica flash chromatography. This gave a dark yellow solid, 5.12 g, 25 mmol, 60% yield. UV analysis (methanol) showed a single peak with λmax=300 nm. Mass spectrometry (MALDI-TOF with a gentisic acid matrix) gave m/z=203.8 (for C11H12N2O2=204.23). 1H NMR:δ=1.97 (s, 6H), 2.95 (s, 3H), 8.58 (d, J=10 Hz, 1H), 8.70 (s, 1H), 8.78 (d, J=10 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
According to General Method 1A, 23 g (105 mmol) of methyl 5-bromonicotinate and 26 g (126 mmol, 1.2 eq.) of 4-trifluoromethoxyphenylboronic acid were reacted. Yield: 14 g (41% of theory)