Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[NH:11][C:10]=3[O:9][C:8]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].ClCC([Si](C)(C)C)[CH2:36][O:37][CH2:38][CH:39]([Si:42]([CH3:45])([CH3:44])[CH3:43])CCl>CN(C=O)C.CC(=O)OCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH2:36][O:37][CH2:38][CH2:39][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:10]=3[O:9][C:8]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)C(CCl)COCC(CCl)[Si](C)(C)C
Reactant: O=c1[nH]c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a mixture of 5-(4-chlorobenzyl)-6-(3-chlorophenyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (38.7 mg, 0.1 mmol) and K2CO3 (13.8 mg, 0.1 mmol) in DMF (1 mL) at 0° C. was added chloromethyl-2-trimethylsilylethyl ether (33.4 mg, 0.2 mmol). The reaction was stirred at 0° C. for 1 h then diluted with EA (10 mL) and water (3 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1) to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (31 mg, 60.7% yield) as a colorless oil. LCMS: MH+ 517 and TR=2.196 min.
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.C([N:37]([CH:40]([CH3:42])[CH3:41])[CH2:38]C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C1(CN)CC1>CN(C)C=O>[CH:40]1([N:37]([CH3:38])[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([O:24][CH:21]3[CH2:20][CH2:19][N:18]([C:7]4[N:8]=[C:9]([NH:11][CH:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[C:10]5[S:2](=[O:1])[CH2:3][CH2:4][C:5]=5[N:6]=4)[CH2:23][CH2:22]3)=[CH:33][CH:32]=2)[CH2:41][CH2:42]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(OC2CCN(c3nc4c(c(NC5CCOCC5)n3)S(=O)CC4)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(OC2CCN(c3nc4c(c(NC5CCOCC5)n3)S(=O)CC4)CC2)cc1)C1CC1
Temperature: 25 °C

Procedure:
55 mg of Example 184 (see 40.) are placed in 2 ml dimethylformamide, then 81 l diisopropylethylamine and 53.1 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min 13.8 mg cyclopropylmethylamine hydrochloride are added. The reaction mixture is stirred at ambient temperature until there is no further reaction and the product is purified directly by preparative HPLC (method B). 30 mg of Example 242 are obtained as a solid.
Reaction SMILES: [N:1]1([C:8](OC(C)(C)C)=O)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:16][CH:17]=C>ClCCl>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH:16]=[CH2:17]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: C=CCBr
Solvent: ClCCl
Product: C=CCN1CCCNCC1
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of tert-butyl 1-homopiperazinecarboxylate (9.73 mL, 50 mmol) in dichloromethane (250 mL) was added PS-TBD resin (40 g, 100 mmol) and 3-bromoprop-1-ene (4.33 mL, 50 mmol) dropwise at 25° C. The mixture was stirred for 2 h. The PS-TBD was filtered off and the filtrate evaporated to dryness, redissolved in MeOH/EtOAc (1:9) and then filtered through a short silica column. The filtrate obtained was evaporated to dryness, treated with TFA (20 ml) and then stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (50 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford 1-prop-2-enyl-1,4-diazepane (4.07 g, 58.0%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][OH:9].Br[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[ClH:42]>>[ClH:42].[ClH:42].[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][O:9][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Brc1cccnc1
Reactant: CN1CCCC[C@@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCCC[C@@H]1COc1cccnc1
Temperature: 90 °C
Reaction time: 120 h

Procedure:
The compound from step 42b (553 mg, 4.28 mmol) was allowed to react with 3-bromopyridine (0.43 mL, 4.50 mmol), cuprous bromide (0.165 g, 0.86 mmol), triphenylphosphine (0.449 g, 1.7 mmol) and potassium carbonate (0.592 g, 4.28 mmol). The reaction mixture was heated to 90° C. and stirred for 120 hr, then cooled to 25° C., acidified with HCl (1.5M; 35 mL) and washed with ethyl acetate (4×50 mL). The aqueous layer was basified with saturated aqueous potassium carbonate, and the product was extracted with chloroform (6×50 mL), dried (MgSO4) and concentrated in vacuo to an oil. The crude product was purified by chromatography on silica gel (CH2Cl2 /EtOAc/MeOH/NH4OH 50:50:4:1) to yield the free base of the title compound (0.048 g). The amine was treated as in example 1b to yield the title compound as a hygroscopic semisolid (0.024 g, 2%). MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (D2O, 300 MHz) δ:8.37-8.29 (m, 2H), 7.66 (dd, J=8.45, 1.5 Hz, 1H), 7.59-7.57 (m, 1H), 4.63 (dt, J=14.5, 2.4 Hz, 2H), 4.8 (dd, J=11.9, 1.8 Hz, 1H), 3.58-3.53 (m, 2H), 3.20 (m, 1H), 2.93 (s, 3H), 2.05-1.60 (m, 5H). Anal. calc. for C12H20Cl2N2O·2.0 H2O: C, 45.72; H, 7.67; N, 8.89. Found: C, 45.82; H, 7.93; N, 8.84. [α]D23 -1.14° (c=0.71 in MeOH).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1([O:45][C@H:44]([CH2:46]O)[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:67]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:9][CH2:10][C:11]1([O:45][C@H:44]([CH2:46][I:67])[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(COC(=O)c2ccccc2)O[C@H](CO)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC1(COC(=O)c2ccccc2)O[C@H](CI)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
In DMF (16 ml) was dissolved methyl 1,3,4,5-tetra-O-benzoyl-D-ido-2-heptulopyranoside (950 mg). To the solution were added triphenyl phosphine (1.65 g) and N-iodosuccinimide (1.2 g). The mixture was stirred at room temperature overnight. To the mixture was added ice-water (100 ml). The resulting oily substance was subjected to extraction with ethyl acetate. The ethyl acetate extract was washed with saturated sodium thiosulfate solution, 2N hydrochloric acid and saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was chromatographed on a column of silica gel (200 ml) with toluene-ethyl acetate (10:1). The eluate was concentrated to dryness under reduced pressure to give a white powder (780 mg) of methyl 1,3,4,5-tetra-O-benzoyl-7-deoxy-7-iodo-D-ido-2-heptulopyranoside.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[N:8][N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=3)[CH:11]=2)=[CH:14][CH:15]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(-n2cc(Oc3ccc(N)cc3)cn2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2cc(Oc3ccc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3)cn2)cc1
Temperature: 27.5 °C

Procedure:
4-(1-p-Tolyl-1H-pyrazol-4-yloxy)-phenylamine (100 mg, 0754 mmol), 2,4 Dichloro-benzenesulfonyl chloride (92 mg, 0.754 mmol) was taken in chloroform and 0.2 ml of pyridine was added and the reaction mixture was stirred at 20-35° C. for 3 and half an hours. Chloroform was removed under vacuum and the product was purified though column chromatography using petroleum ether and ethyl acetate.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.CCCCCC>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[CH:7]=[O:8])([O-:12])=[O:11]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 5-fluoro-2-nitrobenzaldehyde (15.00 g, 0.089 mol), phenol (9.12 g, 0.098 mol), and K2CO3 (13.5 g, 0.089 mol) in 200 mL of DMF was heated at 120° C. for 50 min. The reaction mixture was cooled and concentrated in vacuo. To the residue was added EtOAc (500 mL) and H2O (500 mL). The layers were separated, and the EtOAc extract was concentrated. The residue was purified on silica gel using 20% EtOAc-hexane as eluent. The product containing fractions were combined and concentrated to yield a yellow oil which solidified on standing. This material was dissolved in a minimal quantity of EtOAc and hexane, and the resulting solution was cooled in a dry ice acetone bath. Filtration yielded 2-nitro-5-phenoxy-benzaldehyde as a light yellow solid. The filtrate was concentrated in vacuo to yield additional 2-nitro-5-phenoxy-benzaldehyde.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:16].[Na+].Cl>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[OH:16][C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [OH-]
Reactant: CSc1ccc(C(=O)C2CCCC2)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)C2(O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of the ketone from Step 1 (7.2 g, 32.7 mmol) in 4.7 ml CCl4 and 9.6 ml toluene was added Aliquat 336 (2.11 g, 5.20 mmol) and powdered NaOH (2.88 g, 71.9 mmol) and the mixture was stirred for 16 h at r.t. To the brown mixture was added 100 ml of 5% aq. HCl and extracted with EtOAc (4×100 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel (20% EtOAc/hexane) gave 5.4 g of the title compound as a white waxy solid (70%).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24]C)=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:15]([O:14][C:12]([N:10]1[CH2:11][C@@:7]([C:4]2[CH:3]=[CH:2][C:1]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:6][CH:5]=2)([S:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH2:8][C@H:9]1[C:22]([OH:24])=[O:23])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@@](SC[Si](C)(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.2 %

Procedure:
To a solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-1,2-dicarboxylate (472 mg, 0.884 mmol) in THF (10 mL) and MeOH (10 mL) was added premade solution of Lithium hydroxide monohydrate (74.2 mg, 1.769 mmol) in Water (10 mL). The formed white slurry was stirred at room temperature for 3 days. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated to afford the desired product (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-2-carboxylic acid (460 mg, 0.797 mmol, 90% yield) as a wax. This product was used for the next reaction without further purification. LC-MS (retention time: 3.43 min, method B), MS m/z 520 (M+H).
Reaction SMILES: I[CH:2]([CH:8]([CH3:16])[C:9]([Cl:15])([F:14])[C:10]([Cl:13])([F:12])[F:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>C(O)C>[N:17]([CH:2]([CH:8]([CH3:16])[C:9]([Cl:15])([F:14])[C:10]([Cl:13])([F:12])[F:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:18]=[N-:19]
Reactant: CCOC(=O)C(I)C(C)C(F)(Cl)C(F)(F)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(N=[N+]=[N-])C(C)C(F)(Cl)C(F)(F)Cl
Yield: 122.5 %

Procedure:
Then in 350 ml of 80% ethanol, 31 g (0.0080 mol) of ethyl 2-iodo-3-methyl-4,5-dichloro-4,5,5-trifluoropentanoate and 26 g (0.040 mol) of sodium azide were refluxed at an elevated temperature for 22 hours. By treating the product by following the procedure of Example 1, there was obtained 3.03 g (0.0098 mol, yield of 12%) of ethyl 2-azido-3-methyl-4,5-dichloro-4,5,5-trifluoropentanoate having b.p. 94° C./4 mm, nD20 1.4420, νN3 2113 cm-1 and νC=O 1748 cm-1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cccc(CCc2ccccc2OCC2CCCN(C)C2)c1
Yield: 76.7 %

Procedure:
Following a procedure similar to that described in Example 38, 850 mg of 1-t-butoxycarbonyl-3-{2-[2-(3-methoxyphenyl) ethyl]phenoxymethyl}piperidine (prepared as described in Example 49) were reacted with 113 mg of lithium aluminum hydride. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 520 mg (yield 76%) of the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:16](I)[CH3:17].O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:16]([N:6]1[C:2](=[O:1])[CH2:3][CH2:4][C@H:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:17]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN1C(=O)CC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,1-dimethylethyl 5-oxo-L-prolinate (2.7 g, 12 mmol, prepared as described in Synth. Comm., 2005, 35(8), 1129) was added to a suspension of sodium hydride (0.428 g (60% suspension in oil), 10.7 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 5 minutes. Ethyl iodide (1.67 g, 10.7 mmol) was then added and the mixture was heated at 40° C. for 2 hrs. A further quantity of sodium hydride (0.24 g) was added and stirring continued overnight at room temperature. An additional quantity of ethyl iodide (0.86 ml) was added to the mixture at this stage and the mixture was left to stand at room temperature over the weekend. Water (˜10 ml) was added to the mixture and this was stirred for 15 minutes. The tetrahydrofuran was evaporated and the remaining aqueous layer was extracted with dichloromethane (2×50 ml) and a 3:1 mixture of chloroform and isopropanol (50 ml). The combined organic layers were filtered through a hydrophobic frit and evaporated to give a yellow oil. Toluene was added to the mixture and then evaporated to a yellow oil once more. This material was purified by automated silica flash-column chromatography (Biotage SP4), eluting with a 15-100% gradient of ethyl acetate in hexane, to give pure 1,1-dimethylethyl 1-ethyl-5-oxo-prolinate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH2:17][CH3:18].[Cl-].[Na+]>CN(C)C=O.O>[CH2:16]([NH:19][C:13]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:15])[CH2:17][CH3:18]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitro-1H-indole-2-carboxylic acid (6.95 g, 33.7 mmol) in N,N-dimethylformamide (DMF)/pyridine (1/1, 150 ml) N,N′-carbonyl-diimidazole (5.47 g, 33.71 mmol) was added. The mixture was stirred at 80° C. for 1 h. At 0° C. propylamine (9.96 g, 168.56 mmol) was added. The mixture was stirred at 0° C. for 1 h and then at room temperature for 16 h. The solution was diluted with water (2 I). After addition of sodium chloride the product precipitated. After filtration the residue was washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as a yellow powder.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.[BH4-].[Na+]>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][O:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][CH:11]=1
Reactant: COCCOCCl
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COCCOCOc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled suspension (0° C.) of 60% NaH (660 mg, 16.5 mmol) in THF (35 mL) is added dropwise a solution of 3-hydroxybenzaldehyde (1.89 g, 15 mmol) in THF (15 mL) and the resulting mixture stirred for 20 min. To the mixture is added 2-methoxyethoxymethyl chloride (1.88 mL, 16.5 mmol) and DMPU (5 mL), the cold bath removed and stirred for 1 hr. The reaction mixture is cooled to 0° C. then slowly added 2M NaBH4 (in triglyme) (3.75 mL, 7.5 mmol) and let stir for 1 hr. Slowly quenched with 2N HCl soln (3.9 mL) and diluted reaction mixture with ether. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 60% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. MS (EI) 212 (M)+.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:22][C:23]1[C:24]([F:48])=[CH:25][C:26]([Cl:47])=[C:27]([CH:46]=1)[O:28][C:29]1[CH:43]=[CH:42][C:32]2[N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[S:35][C:31]=2[C:30]=1[C:44]#[N:45]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([NH:22][C:23]1[CH:46]=[C:27]([O:28][C:29]2[CH:43]=[CH:42][C:32]3[N:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:41][CH2:40]4)=[O:38])[S:35][C:31]=3[C:30]=2[C:44]#[N:45])[C:26]([Cl:47])=[CH:25][C:24]=1[F:48])=[O:10]
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Reactant: Cn1ncc(C(=O)O)c1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c(Cl)cc2F)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (68 mg, 0.331 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (34 mg, 26%) as a white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C1(C)C=CC=CC=1>N1CCCCC1.C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(SC)cc1)C(=O)OCC

Procedure:
4-(Methylthio)Benzaldehyde (3.04 g, .02 mol), diethyl malonate (3.20 g. .02 mol), toluene (25 mL), piperidine (4 drops) and acetic acid (2 drops) are mixed and heated at reflux for 2 hours with the water formed being removed azeotropically. The solution is cooled and 25 mL of water added stirring. After separation of the layers, the toluene is evaporated from the organic layer to yield the product, diethyl 2-[[4-(methylthio)phenyl]methylene]propanedioate, in essentially quantitative yield. When dissolved in methylene chloride, the product has an absorption maximum (λmax) at 330 nm in the ultraviolet absorption spectrum. The identity of the product is confirmed by mass spectroscopy analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>C(#N)C>[C:16]1([NH:15][C:4]2[N:5]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[C:2]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc(Nc2ccccc2)nc(Nc2ccccc2)n1
Reactant: NCc1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: c1ccc(Nc2nc(NCc3ccncc3)nc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 200 mg portion of 6-chloro-N,N′-diphenyl-1,3,5-triazine-2,4-diamine was dissolved in 10.0 ml of acetonitrile, and 145 mg of 4-(aminomethyl)pyridine and 0.585 ml of diisopropylethylamine were added thereto and stirred overnight at 80° C. The reaction solution was cooled down to room temperature, and then mixed with water and extracted with chloroform. The organic layer was washed with 5% citric acid and saturated brine and then dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, the thus obtained residue was applied to a silica gel column chromatography and eluted with ethyl acetate:n-hexane (2:1), and then the thus obtained crude product was crystallized from ethyl acetate/n-hexane, thereby obtaining 107 mg of N,N′-diphenyl-N″-(4-pyridylmethyl)-1,3,5-triazine-2,4,6-triamine as light red crystals.