Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:6][C:5]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:3]1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(Cl)nc1C(F)(F)C(F)(F)F
Yield: 71 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)C.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][C:36]=1[C:43]([F:46])([F:45])[F:44]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:21]2[CH2:22][CH:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][C:7]([CH3:32])([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:6]([OH:5])=[O:33])=[CH:14][CH:13]=3)[N:19]([CH3:24])[C:20]2=[O:23])=[CH:37][C:36]=1[C:43]([F:44])([F:45])[F:46]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(F)c(C(F)(F)F)c2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.6 %

Procedure:
NaH (9.2 mg, 0.23 mmol, 60% w/w in mineral oil) is added to a cooled (0° C.) solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (82.0 mg, 0.19 mmol) in DMF (1 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over one hour. After the solution is cooled again to 0° C., 4-fluoro-3-(trifluoromethyl)benzyl bromide (148 mg, 0.57 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for one hour. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is dissolved in methanol (5 ml), treated with 5N NaOH (0.5 ml), and stirred for 18 hours at ambient temperature. After concentration to remove methanol, the residue is partitioned between diethyl ether and water. The aqueous layer is adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified by MS/LC to yield an oil (41 mg, 37%).
Reaction SMILES: [F:1][C@@:2]1([C:14]([O:16]C)=[O:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[OH-].[Na+]>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@:2]([F:1])([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@]1(F)CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of #167 (238 mg, 0.963 mmol, 1 eq.) dissolved in methanol (2.6 mL) was added an aqueous solution of sodium hydroxide (2.5 M, 0.88 mL) and the reaction was stirred at room temperature for 3 hours. The reaction was then quenched with 10% aqueous citric acid (5 mL) and ethyl acetate (100 mL) was added, and the layers were separated. The organic layer was washed with 10% citric acid, water, and brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford #169 as a white solid (221 mg, 99%). 1H NMR (400 MHz, CDCl3), δ 3.96-3.69 (m, 3H), 3.59 (m, 1H), 2.59-2.33 (m, 2H), 1.51 (s, 9H). LC-MS (Protocol Q1): m/z 232.1 [M−H+], retention time=0.67 minutes. Chiral HPLC retention time: 3.95 min (purity=98%)(Column: Chiralpak AD-H, 4.6 mm×25 cm, mobile phase 5-60% CO2/Methanol, flow rate 3.0 mL/min); Optical rotation: [α]D25−3.6 (c=0.55, MeOH)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24]Br)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24][N:11]2[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[CH:9]=[CH:10]2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: Cn1ncc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 3-(4-chlorobenzoyl)benzyl bromide (681 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 2 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl-acetate=1:3) to provide the title compound as white powder (630 mg, yield 83%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:26][CH2:27]Cl)(=[O:25])[CH2:23][CH3:24]>CC(C)=O>[C:22]([O:26][CH2:27][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])(=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)OCCl
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCC(=O)OCn1ccnc1C(C)c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of the compound of Example 1 (120 mg, 0.6 mmol) and caesium carbonate (731 mg, 1.8 mmol) in acetone (4 ml), under nitrogen, was added chloromethyl propionate (Eur. J. Pharm. Sci: 24; 5; 2005; 433-440, 183 mg, 1.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered and the filtrate was concentrated in vacuo.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:17][CH:18]=1)(=[O:34])[CH3:33]
Reactant: Cc1cccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(COc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(C)n1
Reaction time: 48 h

Procedure:
A mixed solution of 5-{4-[2-hydroxy-2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione (350 mg), pyridine (5 ml) and acetic anhydride (0.2 ml) was allowed to stand at room temperature for 2 days, and then poured in water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of the solvent. The residue was chromatographed on a silica gel (20 g) column, and elution was effected with benzene-acetone (15:1, V/V) to give 5-{4-[2-acetoxy-2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione in the form of an oily substance. Yield of 360 mg (89.8%). IR (neat): 1740, 1690, 1230 cm-1. NMR (CDCl3)δ: 211(3H,s), 2.51(3H,s), 3.02 (1H,dd,J=14 and 9 Hz), 3.41(1H,dd,J=14 and 4 Hz), 4.37(2H,d, J=5 Hz), 4.44(1H,dd,J=9 and 4 Hz), 6.13(1H,t,J=5 Hz), 6.83(2H, d,J=9 Hz), 7.09(2H,d,J=9 Hz), 7.0-7.7(3H,m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.S(O)(O)(=O)=O.[CH3:42][N:43]1[C:47]([NH2:48])=[C:46]([NH2:49])[CH:45]=[N:44]1.C(N(CC)C(C)C)(C)C>ClCCl.O1CCCC1>[NH2:48][C:47]1[N:43]([CH3:42])[N:44]=[CH:45][C:46]=1[NH:49][C:11](=[O:13])[CH:10]([OH:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc(N)c1N
Reactant: CC(C)(C)OC(=O)NCC(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)C(O)CNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[(tert-butoxycarbonyl)amino]-2-hydroxypropanoic acid (1.61 g) in dichloromethane (8 ml) and tetrahydrofuran (8 ml) were added HOBT (1.59 g) and WSCD HCl (3.01 g), and the mixture was stirred at room temperature for 1 hour. The solution was cooled to 0° C., and 1-methyl-1H-pyrazole-4,5-diamine sulfate and N,N-diisopropylethylamine (4.1 ml) were added. The mixture was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure to give crude tert-butyl {3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-2-hydroxy-3-oxopropyl}carbamate, which was used in the next reaction without further purification.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]2[O:54][C:39]3=[CH:40][N:41]=[C:42]([C:44]4[CH:49]=[CH:48][C:47]([C:50](O)=[O:51])=[CH:46][C:45]=4[F:53])[CH:43]=[C:38]3[CH2:37]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)C(C)C)C.N>CN(C)C=O.CO.O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]2[O:54][C:39]3=[CH:40][N:41]=[C:42]([C:44]4[CH:49]=[CH:48][C:47]([C:50](=[O:51])[NH2:6])=[CH:46][C:45]=4[F:53])[CH:43]=[C:38]3[CH2:37]2)[CH2:32][CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(=O)O)cc4F)ncc3O2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(N)=O)cc4F)ncc3O2)CC1
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (120 mg) is added to a solution of 4-[5-(4-carboxy-2-fluoro-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (150 mg) and ethyldiisopropylamine (100 mL) in N,N-dimethylformamide (1.50 mL) at room temperature. The mixture is stirred for 10 min prior to the addition of a solution of ammonia in methanol (7 M; 0.50 mL). The resulting mixture stirred at room temperature for 2 h. Water is added and the mixture is extracted with ethyl acetate/methanol. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate). The crude product is triturated with ethyl acetate, filtered off, washed with diethyl ether and dried to give the title compound. LC (method 7): tR=1.28 min; Mass spectrum (ESI+): m/z=442 [M+H]+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(O)C=CC=CC=1.C(O)CC/C=C/CCCCC.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]/[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCC/C=C/CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CCCCC/C=C/CCCOc1ccc(C(=O)OC)cc1
Yield: 80 %

Procedure:
DEAD (641 mg, 3.68 mmol), phenol 34 (487 mg, 3.2 mmol), alcohol 26i (500 mg, 3.2 mmol), and TPP (966 mg, 3.68 -mmol) in 16 ml anhydrous ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5 to 90/10 (v/v, Hex/EtOAc). Evaporation of the solvent yielded 748 mg (80%) of colorless liquid.
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]5[N:37]=[C:38]([C@@H:41]6[CH2:46][C@:45]7([CH3:47])[C@@H:43]([CH2:44]7)[N:42]6C(OC(C)(C)C)=O)[NH:39][CH:40]=5)=[CH:32][CH:31]=3)[CH:24]=[CH:23]4)[N:19]=2)[CH2:13][C@:12]2([CH3:55])[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1.CO>[CH3:47][C@:45]12[CH2:44][C@H:43]1[NH:42][C@H:41]([C:38]1[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:14]7[CH2:13][C@:12]8([CH3:55])[C@@H:10]([CH2:11]8)[NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=1)[CH2:46]2
Reactant: CC(C)(C)OC(=O)N1[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@@]8(C)C[C@H]8N7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)C[C@@]2(C)C[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@]12C[C@@H](c3nc(-c4ccc(-c5ccc6cc(-c7c[nH]c([C@@H]8C[C@@]9(C)C[C@H]9N8)n7)ccc6c5)cc4)c[nH]3)N[C@@H]1C2
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (5 mL) was added to tert-butyl (1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (48 mg. 0.066 mmol) in MeOH (1 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 44 mg). LC-MS retention time 2.82 min; calcd. for C34H35N6: 527.29 m/z Found 527.26 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9](=[O:11])[CH3:10])=[N:7][CH:6]=[N:5]1.Cl.C([O-])(O)=O.[Na+].[CH3:18][O:19][C:20](=O)[O:21]C>>[CH3:3][N:4]1[C:8]([C:9](=[O:11])[CH2:10][C:20]([O:19][CH3:18])=[O:21])=[N:7][CH:6]=[N:5]1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ncnn1C
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Product: COC(=O)CC(=O)c1ncnn1C
Temperature: 90 °C

Procedure:
NaH (7.84 g, 196 mmol of a 60% dispersion in oil) was added portionwise to a solution of 6.18 g (34.5 mmol) of 1-(1-methyl-1H-1,2,4-triazol-5-yl)ethanone (Ohta, S.; Kawasaki, I.; Fukuno, A.; Yamashita, M.; Tada, T.; Kawabata, T. Chem. Pharm. Bull. (1993), 41(7), 1226-31) in 100 ml dimethylcarbonate. The mixture was heated to 90° C. for 2 hour forming a thick slurry. After cooling to room temperature, the mixture was slowly transferred to 1N HCl over ice. The mixture was brought to about pH 7 with NaHCO3, then saturated with NaCl and extracted 4 times with EtOAc. The combined EtOAc layers were dried over anhydrous MgSO4, then concentrated to give an oil that was chromatographed on silica gel (100% DCM followed by gradient elution to 50% EtOAc in DCM). The title compound (5.3 g) was obtained as an oil. NMR: 3.78 (s, 3H), 4.11 (s, 2H), 4.22 (s, 3H), 7.94 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20])([O-])=O>[Pd].O.CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20]
Reactant: CCCC1CC(=O)N(CNc2ccccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCC1CC(=O)N(CNc2ccccc2N)C1
Reaction time: 16 h

Procedure:
Palladium on charcoal (10% wt) was added to a solution of (2-nitrophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a28 (1 eq, 2.747 g, 9.905 mmol) and NH4CO2H (5 eq, 49.9 mmol, 3.123 g) in water and methanol (1/1 (v/v), 35 ml). The resulting slurry was kept under agitation during 16 hours at room temperature, then filtration over celite and evaporation of the crude mixture gave (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (2.232 g, 91%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=[O:4].[S:25]1[CH:29]=[C:28]([CH:30]=O)[N:27]=[CH:26]1.CN(C)C=O.ClCCCl.C(Cl)Cl>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:2]([NH:1][CH2:30][C:28]2[N:27]=[CH:26][S:25][CH:29]=2)[C:3]([NH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[N:8][CH:7]=2)=[O:4])=[CH:23][CH:22]=1
Reactant: O=Cc1cscn1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cnc(-c2ccncc2)s1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2ccncc2)s1)[C@H](Cc1ccc(F)cc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a mixture of (S)-2-amino-3-(4-fluorophenyl)-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide (0.090 g, 0.20 mmol), thiazole-4-carbaldehyde (0.022 g, 0.20 mmol), N,N-dimethylformamide (0.014 g, 0.20 mmol) and 1,2-dichloroethane (0.020 g, 0.20 mmol) was added Reactant 3 (0.19 g, 0.89 mmol). The resulting mixture was allowed to stir at rt overnight. The mixture was directly purified HPLC to give 56 mg of (S)-3-(4-Fluorophenyl)-N-(2-(pyridin-4-yl)thiazol-5-yl)-2-(thiazol-4-ylmethylamino)propanamide 5.2. 400 MHz 1H NMR (CD3OD) δ: 9.09 (d, J=4.0 Hz, 1H), 8.78 (d, 2H), 8.34 (d, J=8.0 Hz, 2H), 7.80 (d, 1H), 7.74 (s, 1H), 7.24 (dd, J=8.0, 4.0 Hz, 2H), 7.04 (, J=12, 8.0 hz, 2H), 4.54 (d, J=16 Hz, 1H), 4.50 (d, J=16 Hz, 1H), 4.40 (dd, J=12.0, 8.0 Hz, 1H), 3.47 (dd, J=16.0, 8.0 Hz, 1H), 3.26 (dd, J=16.0, 8.0 Hz, 1H). LCMS (ES+) m/z 440.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:21]=[C:12]3[C:13]4[C:18]([CH2:19][CH2:20][N:11]3[N:10]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:7][CH:8]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:21]=[C:12]3[C:13]4[C:18]([CH:19]=[CH:20][N:11]3[N:10]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: COc1cccc(-c2nc3c4ccccc4ccn3n2)c1
Reaction time: 6 h
Yield: 70 %

Procedure:
Thirty five grams of wet manganese dioxide, prepared as described by E. Pratt and J. Van de Castle, J. Org. Chem. 26, 2973 (1961) is suspended in 200 ml. of benzene, according to the procedure outlined by J. Goldman, J. Org. Chem. 34, 1979 (1969). The mixture is refluxed for about three hours, then a solution of 2.77 g. (0.010 mole) of 2-(m-methoxyphenyl)-5,6-dihydro-s-triazolo[5,1-a]isoquinoline in 30 ml. of anhydrous benzene is added. Refluxing is prolonged for a further six hours, then the reaction mixture is allowed to stand overnight. 20 Grams of the above manganese dioxide is added and the resulting suspension is refluxed for 8 hours. After cooling, the solid catalyst is filtered off, the benzene solution is dried under vacuum and a residue is obtained which is recrystallized from ethyl acetate. Yield 1.4 g., m.p. 159°-60° C. Alternatively, the title compound may be obtained in a 70% yield by treating at 200°-250° C with about 1.5 equimolecular proportion of sulfur.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH2:25])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(N)c45)[nH]c3c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(NC(=O)c6ccccc6)c45)[nH]c3c2)CC1
Reaction time: 8 h

Procedure:
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine is dissolved in CH2Cl2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][CH:16]=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][CH3:16])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(NC=O)c(OC)cc1OC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(C(=O)OC)c(OC)cc1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 1.60 g portion of methyl 2,4-dimethoxy-5-formylaminobenzoate was dissolved in 20 ml of tetrahydrofuran, and 1.7 ml of borane dimethylsulfide complex was added under ice-cooling, followed by 2 hours of stirring at 60° C. Then, 3 ml of methanol and 4 ml of concentrated hydrochloric acid were added, followed by stirring at 75° C. for a while and then spontaneously cooled. The thus precipitated product of interest was collected by filtration, washed with tetrahydrofuran and then dried under a reduced pressure to give 1.08 g of methyl 2,4-dimethoxy-5-methylaminobenzoate.