Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: CNC
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Product: CN(C)c1nnc(C#N)c(N2CCc3ccccc3CC2)n1

Procedure:
In an analogous manner as described in example 2, reaction of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile with dimethylamine (33% solution in absolute ethanol) in a sealed tube at 110° C. yielded 3-dimethylamino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a light brown amorphous solid; MS: 295 (M+H)+.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:5]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH:4]=[O:3]
Reactant: COC(=O)c1ccc(CCC=CO[Si](C)(C)C)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CCC(Br)C=O)cc1
Yield: 100.8 %

Procedure:
To 4.46 g (16 mmol) of methyl 4-(4-trimethylsilyloxy-3-butenyl)benzoate, prepared in Preparation 1, in 16 ml carbon tetrachloride at -20° C. was slowly added 2.56 g (16 mmol) of bromine in 16 ml carbon tetrachloride over 4 hours. The mixture was allowed to come to room temperature then decanted from a small amount of insoluble material. The solvent was removed by vacuum rotary evaporation to give 4.60 g of 2-bromo-4-(4-carbomethoxyphenyl)butanal. Chromatography purification (silica; hexane--ethyl acetate 7:3) of the above product gave 4.0 g in a yield of 87.8 percent. 1H NMR (CDCl3) δ 2.24 (m, 1H), 2.36 (m, 1H), 2.81 (m, 1H), 2.90 (m, 1H), 3.90 (s, 3H), 4.16 (m, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.97 (d, J=8.2 Hz, 2H), 9.46 (d, J=2.1 Hz, 1H); 13C NMR (CDCl3) δ 32.5, 32.7, 51.7, 54.3, 128.3, 128.4, 129.8, 145.0, 166.6, 192.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a slurry of N-{3-[(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (23, 58 mg, 0.059 mmol) and K2CO3 (139 mg, 1.008 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (2 mL), was added thiophenol (61 μL, 0.590 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. The crude product was purified by preparative reverse-phase HPLC (gradient: 59.9% MeCN, 40% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 10 min; retention time=7.6 min) to afford 7 (15 mg, 32%) mp 101-104° C.; 1H NMR (500.13 MHz, CDCl3) δ 9.54 (br s, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.42 (br s, 1H), 8.01 (t, J=5.7, 1H), 7.82 (t, J=5.7 Hz, 1H), 6.39 (d, J=6.4 Hz, 1H), 5.36 (d, J=4.7 Hz, 1H), 3.43 (m, 1H), 3.22 (m, 1H), 3.11 (m, 2H), 2.93-2.84 (m, 3H), 2.39-2.28 (m, 2H), 2.22 (t, J=7.0 Hz, 2H), 2.04 (t, J=7.4 Hz, 2H), 1.97-0.94 (m, 36H), 0.92 (s, 3H), 0.86 (d, J=6.5 Hz, 3H), 0.84 (d, J=2.4 Hz, 3H), 0.82 (d, J=2.4 Hz, 3H), 0.61 (s, 3H); 13C NMR (125 MHz, DMSO d6) δ 171.9, 170.9, 145.1, 144.4, 144.1, 138.5, 137.9 122.4, 120.5, 99.0, 56.6, 56.0, 55.5, 49.3, 43.3, 41.8 (×2), 41.6, 40.5, 36.4, 36.1 (×2), 35.6, 35.5 (×2), 35.3, 35.2, 35.1, 34.3, 31.2, 27.7, 27.4, 27.3, 26.3, 26.0, 24.9, 24.4, 23.8, 23.2, 22.6, 22.4, 20.4, 18.7, 18.5, 11.6; IR (film) νmax 3257, 3093, 2940, 2858, 1636, 1548, 1377 cm−1; CI m/z 790.5605 (MH+, C45H72N7O5 requires 790.5595).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.Cl[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][NH:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(CC=C)c1nc(NCC(=O)OC)n2oc(=O)nc2n1
Reaction time: 21 h

Procedure:
3.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are dissolved in 100 ml. of acetone and treated with 4 ml. of methyl chloroacetate and 4 g. of potassium carbonate. The mixture is vigorously stirred for 21 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride and water and extracted twice with methylene chloride. The combined organic extracts are dried over potassium carbonate and evaporated under reduced pressure. The crude product is chromatographed over silica gel using a mixture of methylene chloride and methanol (99:1) for the elution, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}glycine methyl ester which is recrystallized from acetone and petroleum ether; melting point 173°-174° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl.[OH-].[Na+].C(OCC)(=O)C>C1COCC1>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[N:12]([CH3:18])[C:13](=[O:17])[C:14]([CH3:16])=[CH:15][C:10]=1[C:8]([NH:7][O:6][CH2:5][CH2:4][OH:3])=[O:9]
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (170 g, 0.35 mol), under nitrogen, in THF (850 mL) was added 2M HCl (318 mL), over 15 minutes at 17-22° C. After 1 hour the reaction was complete (as indicated by HPLC) and a solution of 2M sodium hydroxide (318 mL) was added, over 10 minutes, keeping the temperature at approximately 22° C. The pH of the mixture was approximately 8. The mixture was then partitioned with MIBK (1.02 L) and the lower aqueous layer was separated and discarded. The volume of the organic solution was then reduced by distillation, at ambient pressure and with a jacket temperature of 85-95° C. After the removal of 750 mL solvent the rate of distillation had slowed considerably and the mixture was cooled to approximately 22° C. Crystalline 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide Form 2 (1 g, seed, prepared as described in Example 16C) was added to the mixture followed by ethyl acetate (170 mL). After 5 minutes the mixture began to crystallize and iso-hexane (1.7 L) was added at 23-25° C. over 50 minutes. The slurry was held at 25° C. for 80 minutes and then filtered. The solid was washed with iso-hexane (680 mL) then dried in vacuum oven at 30° C. to provide the title material (147 g, 0.31 mol, 89% yield). 1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, ArH), 7.55 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.52 (˜t, 1H, J 8.5 Hz, ArH), 4.91-4.35 (bs, 1H, OH), 3.74 (t, 2H, J 5 Hz, OCH2), 3.51 (˜t, 2H, J 5 Hz, OCH2), 3.25 (s, 3H, NCH3), 2.02 (s, 3H, ArCH3). MS (ESI) (+) m/z 484 (27%, [M+Na]+), 462 (100%, [M+H]+), 385 (8%), 100 (26%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[N:14]=[C:13]([CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[CH:18][C:17]=2[Cl:23])[C:12]2[C:7](=[CH:8][C:9]([O:24][CH3:25])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl>[Cl:23][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH3:25])=[CH:10][CH:11]=2)[CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:14]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(c1)CN(C(=O)CCl)N=C2Cc1c(Cl)cncc1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CN(C(=O)CN1CCOCC1)N=C2Cc1c(Cl)cncc1Cl
Yield: 52.6 %

Procedure:
A solution under N2 and stirring of 2-chloro-1-[4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1H-phthalazin-2-yl]-ethanone (1.3 g, 3.26 mmoles), prepared as described in example 81, in dry CHCl3 (15 ml), at room temperature, was added with morpholine (0.85 g, 9.78 mmoles) and refluxed for 20 hours. The mixture was poured into water/ice, the phases separated and the organic one was washed with water, anhydrified and brought to dryness to give a solid which was crystallised from acetonitrile (45 ml) to give 0.77 g of the title compound (yield: 53%). m.p.: 180-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]=[CH:15][CH:16]=[CH2:17]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]=[CH:15][CH2:14][O:13]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(N=O)c(Cl)c1
Reactant: C=CC=C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(N2CC=CCO2)c(Cl)c1
Temperature: 0 °C

Procedure:
1.00 g (5.01 mmol) methyl 3-chloro-4-nitroso-benzoate are placed in 10 ml chloroform and a freshly prepared solution of 1.10 g (20.3 mmol) butadiene in 6 ml chloroform is added dropwise with stirring at 0° C. The reaction mixture is stirred for 30 minutes at 0-10° C. and for 16 hours at ambient temperature, evaporated down i. vac. and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[CH:17]=[N:18]O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[C:17]#[N:18]
Reactant: O=c1c(C=NO)c(Cl)ccn1-c1c(F)cccc1F
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)ccn(-c2c(F)cccc2F)c1=O
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a solution of 4-chloro-1-(2,6-difluorophenyl)-3-((hydroxyimino)methyl)pyridin-2(1H)-one obtained in Step D (800 mg) in acetonitrile (7.0 mL) was added phosphorus oxychloride (0.341 mL) at room temperature. The reaction mixture was heated at 100° C. for 1 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (600 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]([CH2:14][CH:15]=[CH2:16])[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.N1C=CC=C[CH:20]=1.CC(OC(C)=O)=O>O>[C:11]([CH:10]([NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1)[CH2:14][CH:15]=[CH2:16])(=[O:13])[CH3:20]
Reactant: c1ccncc1
Reactant: C=CCC(NC(=O)c1ccc(OC)cc1)C(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=CCC(NC(=O)c1ccc(OC)cc1)C(C)=O
Reaction time: 0.75 h

Procedure:
To a solution of 8.41 g of the above prepared 2-(4-methoxy-benzoylamino)-pent-4-enoic acid (33.7 mmol) was added successively 21.2 ml of pyridine and 15.95 ml of Ac2O (5 eq.). The reaction mixture was then kept for 45 min. at 90°. After cooling, 15.8 ml of water was added and the mixture again kept for 30 min. at 85° to ensure complete hydrolysis. Afterwards, it was poured onto crashed ice/HCl, extracted twice with AcOEt, washed with 2N HCl and water, and dried over natrium sulfate. Evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3) afforded 6.45 g of the title compound as yellow solid of mp. 58-59°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[CH3:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Product: Cc1cnc(CNC(=O)c2sc(-n3ccc(O)cc3=O)nc2C)cn1
Yield: 14 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 14% yield: 1H NMR (300 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.80 (t, J=5.2 Hz, 1H), 8.59 (d, J=7.8 Hz 1H), 8.44 (s, 2H), 6.26 (d, J=7.8 Hz, 1H), 5.81 (s, 1H), 4.47 (d, J=5.2 Hz, 2H), 2.52 (s, 3H), 2.43 (s, 3H); MS (ES+) m/z 358.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: COc1cccc2c1CCCC2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1CCCC2=NO
Temperature: 80 °C
Yield: 94 %

Procedure:
A solution of 5-methoxy-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.1 g) and sodium carbonate monohydrate (3.6 g). The reaction mixture was heated overnight at 80° C. with a condenser. Cooled to room temperature after approximately seventeen hours, transferred to another flask and concentrated. The residue was triturated in water and filtered to yield the title product as a beige solid (5.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C1COCC1>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CC(C)(C)Cn1c(Cc2ccc(NC(=O)CCC(=O)O)cc2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.626 mmol) in THF (3 ml), succinic anhydride (0.626 mmol) is added. The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is concentrated under vacuum. Purification of the residue by silica gel column chromatography affords the title compound in quantitative yield.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:17]([Br:18])=[CH:16][CH:15]=[CH:14][N:13]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:18][C:17]1[C:12]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: [Zn+]CCc1ccccc1
Reactant: Brc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Brc1cccnc1CCc1ccccc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.0 g) is added to a flask charged with a stir bar, phenethylzinc bromide (0.5 mol/L in tetrahydrofuran, 100 mL), 2,3-dibromopyridine (10.50 g), and tetrahydrofuran (100 ml) and kept under argon atmosphere at room temperature. The resulting mixture is stirred at room temperature for 3 h and at 40° C. for another 16 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→75:25) to afford the title compound as an oil that solidified upon treatment with ether. Yield: 9.32 g (81% of theory); LC (method 1): tR=4.28 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11]CC#C)=[O:10])=[CH:7][C:6]=1[F:17])[C:2]#[CH:3].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[F:17])[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1ccc(OCC#C)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To 50 ml of ethanol were added 10.8 g of 2-propynyl 4-(2-propynyloxy)-3-fluorobenzoate and 30 ml of 15% aqueous sodium hydroxide solution, and the mixture obtained was stirred at room temperature for 2 hours. Then, the reaction mixture was added to hydrochloric acid for acidification. Crystals precipitated were collected by filtration and dried to obtain 8.0 g of 4-(2-propynyloxy)-3-fluorobenzoic acid represented by the formula:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])([O-])=O.[H][H]>[Ni].O1CCCC1.CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1N
Temperature: 25 °C
Yield: 101.3 %

Procedure:
Raney nickel (1 g) was added to a solution of 3-nitro-4-methyl-N-phenyl-benzamide (6.2 g, 24 mmol) in a mixture of tetrahydrofuran (50 mL) and methanol (100 mL) and shaken at room temperature under an atmosphere of hydrogen, initially at a pressure of 50 psi, until the required amount of hydrogen was taken up. The catalyst was removed by filtration, and the filtrate was stripped of solvent by rotary evaporator. The residue was dried under reduced pressure to afford the pure product (5.5 g); m.p. 149-151° C.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][NH:11][C:12](=[O:38])[C@@H:13]([CH2:34][CH2:35][CH2:36][CH3:37])[NH:14][C:15](=[O:33])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C1C=CC=CC=1.[OH-].[Na+]>CO>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:15]([NH:14][C@@H:13]([C:12]([NH:11][CH2:10][C:9]([OH:39])=[O:8])=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 3 h
Yield: 65.2 %

Procedure:
14.9 g (27.5 mmoles) of the protected tripeptide ester obtained in Step 2 above are dissolved in 300 ml of methanol, 55 ml of a 1 n sodium hydroxide solution are added, and the mixture is allowed to stand at room temperature for 3 hours. Thereafter methanol is distilled off under reduced pressure, the aqueous solution is shaken thrice with 15 ml of ethyl acetate, each, and acidified to pH=3 with solid citric acid. The separated substance is filtered off, washed with water and dried in a vacuum desiccator. 8.1 g (65%) of tert.-butoxycarbonyl-L-tyrosyl-D-norleucyl-glycine are obtained; m.p.: 174°-175° C., Rf2 =0.35-0.45, [α]D20 =+2.0° (c=1%, in dimethyl formamide).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl.[CH3:13]O>C(OCC)C>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(Br)cc1C

Procedure:
4-Bromo-2-methylbenzoic acid (5.0 g, 23 mmol) was suspended in methanol (30 mL). To the mixture was added a solution of HCl in diethylether (1.0M, 30 mL). The mixture was refluxed for 24 hours and concentrated to dryness. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the desired compound (5.5 g) as a brown oil.
Reaction SMILES: I[CH2:2][CH2:3][OH:4].C(=O)(O)[O-].[Na+].[CH3:10][O:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][S:17][C@@H:18]2[CH2:22][NH:21][C@H:20]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19]2)=[CH:14][CH:13]=1.[Cl-].[Na+]>CN(C)C=O>[OH:4][CH2:3][CH2:2][N:21]1[CH2:22][C@@H:18]([S:17][CH2:16][C:15]2[CH:27]=[CH:28][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH2:19][C@H:20]1[C:23](=[O:26])[NH:24][CH3:25]
Reactant: OCCI
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCO
Temperature: 40 °C
Reaction time: 24 h

Procedure:
934 μl of 2-iodoethanol and 1.01 g of sodium bicarbonate were added, whilst ice-cooling, to a solution of 2.80 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine dissolved in 18 ml of dry dimethylformamide, and the mixture was stirred at 40° C. for 24 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 15:1 by volume mixture of ethyl acetate and methanol), to afford 2.22 g of the title compound as colorless crystals, melting at 88°-89.5° C.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH2:13][CH2:14][N:3]1[C:4]=23.[CH:19](O)=O>C=O>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([N:15]([CH3:19])[CH2:16][CH:17]=[CH2:18])[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: C=CCNC1CCN2C(=O)OCc3cccc1c32
Reactant: O=CO
Agent: C=O
Product: C=CCN(C)C1CCN2C(=O)OCc3cccc1c32
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6,7-Dihydro-3-oxo-7-allylamino-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5.86 g) was dissolved in a solution of formic acid (7 ml) and 35% formalin (7 ml), and the solution was stirred for 2 hours at 90° C. Formic acid and formalin were distilled off under reduced pressure, and to this mixture were added ice water and dichloromethane, and the mixture was adjusted to alkalinic with sodium carbonate. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and distilled off to give 6,7-dihydro-3-oxo-7-(N-methyl-N-allylamino)- 1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5.90 g).