Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([OH:22])=[O:21])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:29]
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Yield: 71 %

Procedure:
A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (1.5 g, 0.00503 mole) in absolute ethanol was acidified with 0.5 ml of concentrated sulfuric acid and refluxed under nitrogen for three days. The solution was evaporated to approximately one-third of its original volume (reduced pressure), and saturated sodium bicarbonate solution and ethyl acetate were added. The layers were separated, the aqueous layer was re-extracted with ethyl acetate and the combined organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a solid. The solid was dissolved in hot absolute ethanol and filtered hot. Upon cooling to room temperature, a solid formed which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 1.17 g (71%) of title compound, mp 191.5°-193.5° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1.C(Cl)Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:12]1([C:18]#[C:19][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)c1cccc(C#Cc2ccccc2)c1

Procedure:
Methyl 3-iodobenzoate, phenylacetylene (1.5 eq.) and Pd(PPh3)2Cl2 (5 mol %) in piperidine (3 eq.) was heated at 70° C. for 30 minutes. The solidified residue was dissolved with CH2Cl2 and water and poured onto HCl 2N. The acidic phase was extracted three times with CH2Cl2. The combined organic layers were washed twice with HCl 2N, once with water and once with brine. The organic layer was then dried over MgSO4 and concentrated. The resulting residue was purified using SiO2 with petroleum spirit/toluene 70:30 to give methyl 3-phenylethynyl-benzoate as a white solid (quantitative yield). NMR 1H (ppm, CDCl3): 8.20 (t, J4=1.7 Hz, 1H), 7.98 (d, J3=7.9 Hz, 1H), 7.69 (d, J3=7.6 Hz, 1H), 7.54-7.50 (m, 2H), 7.42 (t, J3=7.8 Hz, 1H), 7.36-7.31 (m, 3H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10])=[O:4].C1C(=O)N([Br:18])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][Br:18])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sccc1CBr
Yield: 89.1 %

Procedure:
3-Methyl-thiophene-2-carboxylic acid methyl ester (1 g, 6.4 mmol) is dissolved in CCl4 (15 mL), and NBS (1.19 g, 6.7 mmol) and benzoyl peroxide (15 mg) are added. The reaction mixture is refluxed for 6 hours, then water is added and the mixture is extracted with EtOAc (3×). The organic layers are dried over MgSO4, filtered and concentrated. The crude product is purified by silica gel column chromatography eluting with 98:2 petroleum ether-EtOAc to give the title compound (1.34 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH:17]2[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[OH2:10].[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH+:16]([O-:33])[CH:17]2[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH+:16]([CH:17]2[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)[O-:33])=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CN1C(=O)COc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)COc2c(C(=O)[NH+]([O-])C3CN4CCC3CC4)cc(Cl)cc21
Product: O
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of 6-chloro-3,4-dihyro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 100 ml of chloroform with cooling at -30° C. is added 4.02 g of 80% metachloroperbenzoic acid, and the system stirred at -20° C. to -25° C. for about 30 minutes. The resultant solution is stirred at room temperature for 20 minutes and ammonia gas is bubbled into the solution at 10°-18° C. The precipitated crystals are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified with column chromatography with a mixed eluent of chloroform and methanol (10:1) and to the residue is added acetonictile. The crystals are collected by filtration and recrystallized form acetonitrile to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide N-oxide hemihydrate, melting at 198°-200° C. with decomposition.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][NH2:5].[CH2:7]([O:14][C:15](SC1N=C(C)C=C(C)N=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([O:14][C:15]([NH:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:6])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCCN
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccccc2)n1
Solvent: CO
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 22.5 %

Procedure:
Into 30 mL of 50% aqueous methanol, was dissolved 1.76 g (20 mmoles) of 1,4-butanediamine followed by the addition of 5.48 g (20 mmoles) of S-benzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (a product of Kokusan Kagaku Co.). The mixture was stirred for 3 hours. Thereafter, the reaction mixture was filtered to remove the precipitated di-N-benzyloxycarbonyl compound [2.09 g (29%) were recovered], and the filtrate was evaporated to dryness. The residue was dissolved in 250 mL of chloroform, washed 5 times with 100 mL of water. The chloroform layer was dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 1.0 g (23% yield) of mono-N-benzyloxycarbonyl-1,4-butanediamine in colorless syrup form.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21](O)=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC1Sc2ccccc2N(CC(=O)O)C1=O)OCc1ccccc1
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid (0.13 mmol) in anhydrous DMF, propylamine (0.13 mmol) is added followed by DIEA (0.13 mmol) and HATU (0.13 mmol). The reaction mixture is stirred overnight and the desired product 2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide is obtained and used in the next step without further purification. MS: (ES+): 428.2 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](#N)C.C(=O)([O-])[O-].[K+].[K+].CI>ClCCl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]([CH3:23])[C:10]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: Cc1c(OCc2ccccc2)c(=O)c(C(O)C(F)(F)F)cn1C
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (2.07 g, 6.6 mmol), acetonitrile (60 mL), potassium carbonate (2.62 g, 19 mmole) and methyl iodide (15 mL, 0.24 mol) was heated to reflux for 30 min. On cooling to RT, the reaction mixture was filtered over a pad of CELITE™, and the filtrate was concentrated in vacuo to give a solid. The solid was dissolved in dichloromethane, and the resulting solution was washed with brine, dried over Na2SO4, filtered and concentrated to afford 3-benzyloxy-1,2-dimethyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.48 g. 70% yield, HPLC Method 1 (Example 24), RT=15.4 min, HPLC purity (peak percent area): 99.9% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.75 (s, 1H), 7.37, (m, 5H), 5.35 (q, J=7.1 Hz, 1H), 5.01 (m, 2H), 3.63 (s, 3H), 2.18 (s, 3H); MS-ESI (m/z) 328.1 [M+1]+, 220.2, 91.2 (100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[N:27][CH:28]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:22][C:23]1[CH:28]=[N:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(N)cn1
Product: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 73.5 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.06 g) and 5-amino-2-isopropylpyridine (0.50 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.08 g) was obtained. melting point: 157.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](=[O:17])[CH:3]=1.[OH-:18].[Na+]>>[NH2:1][C:2]1[NH:7][C:6](=[O:18])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: [OH-]
Reactant: CSc1nc(N)cc(=O)n1Cc1ccccc1
Agent: [Na+]
Product: Nc1cc(=O)n(Cc2ccccc2)c(=O)[nH]1

Procedure:
Reflux 6-amino-3-(phenylmethyl)-2-methylthiopyrimidin-4(3H)-one (2.5 g=10 mmol) in 40 ml 10% aqueous NaOH for four hours. Cool, acidify the solution and collect the precipitate. Water wash and dry to give the title compound, a white solid, EI MS: M+=217.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:15][CH3:16])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][CH:3]=1.CO.[NH2:19][OH:20].[C-]#N.[K+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:15][CH3:16])[CH2:9][CH2:10][C:11]([NH:19][OH:20])=[O:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)CCC(SC)c1ccc(F)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CSC(CCC(=O)NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-4-(methylthio)butanoate (30.0 mg, 0.12 mmol) dissolved in 2 mL of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) was added KCN (4.0 mg, 0.06) and the resulting mixture stirred for 3 days at room temperature. The reaction was quenched by the addition of aqueous 1M HCl (10 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give the title compound (27 mg) as a colorless oil.
Reaction SMILES: C(O)C1C=CC=CC=1.[CH:9]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ON1C(=O)C2=CC=CC=C2C1=O>>[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:22])[CH3:16].[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: OCc1ccccc1
Product: CC(=O)c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In page 762 of the "Lecture Draft II" (1994) of 67th Spring Annual Meeting of Chemical Society of Japan, it is reported that oxidation of an alcohol such as benzyl alcohol or benzhydrol with air using vanadomolybdophosphoriate and N-hydroxyphthalimide provides a ketone such as acetophenone or benzophenone in a high yield, and that oxidation of fluorene or adamantane with oxygen using N-hydroxyphthalimide gives a corresponding adamantanol or fluorenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[C:6]([CH3:12])=[CH:5][CH:4]=1.C(O[C:18](=O)[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=[O:31])N(OC)C)[CH2:22][CH2:21]1)(C)(C)C.[O:33]1[C:38]2[CH:39]=[CH:40][C:41](C=O)=[CH:42][C:37]=2[O:36][CH2:35][CH2:34]1>>[O:33]1[C:38]2[CH:39]=[CH:40][C:41]([CH2:18][NH:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([C:10]4[S:11][C:7]5[C:6]([CH3:12])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=5[N:9]=4)=[O:31])[CH2:24][CH2:25]3)=[CH:42][C:37]=2[O:36][CH2:35][CH2:34]1
Reactant: COc1ccc(C)c2scnc12
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: COc1ccc(C)c2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)nc12

Procedure:
Using 4-methoxy-7-methyl-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a yellowish solid (20 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.N1C=CC=CC=1>O1CCOCC1>[N+:16]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:28]1[CH2:29][CH2:30][N:25]([C:20]2[N:19]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1)([O-:18])=[O:17]
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(c3ncccn3)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
3.0 g (11.2 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 3.7 g (22.4 mmol) of 1-(2-pyrimidyl)-piperazine and 0.9 g (11.2 mmol) of pyridine are boiled under reflux in 50 ml of dioxane. A further 1.9 g (11.6 mmol) of 1-(2-pyrimidyl)-piperazine is added after 6 hours and the reaction mixture is boiled for a further 4 hours. When the reaction mixture has cooled, it is poured out on 300 ml of ice water and the precipitated solid is suction filtered, washed with a small quantity of diethyl ether and recrystallized from 40 ml of 2-methoxyethanol. 3.1 g (70%) of orange red crystals, m.p. 232° to 233° C., are obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]1>CN(C)C=O>[C:87]([O:86][C:84]([N:81]1[CH2:80][CH2:79][CH:78]([NH:77][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH2:32][CH3:33])[CH:24]=2)[CH2:83][CH2:82]1)=[O:85])([CH3:90])([CH3:89])[CH3:88]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a mixture of 0.0905 g (0.196 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 6 mL of dimethylformamide was added 0.0418 g (0.310 mmole) of 1-hydroxybenzotriazole, 0.1146 g (0.302 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1484 g (1.148 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0624 g (0.299 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.1081 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-221) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19]Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[S:33])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1COCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:34]=[C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)[S:33][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Reactant: COc1cccc(NC(N)=S)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC(c2ccc(-c3csc(Nc4cccc(OC)c4)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of {4-[4-(2-bromoacetyl)-phenyl]cyclohexyl}-acetic acid ethyl ester (100 mg, 0.272 mmol) in EtOH/THF (4:1 v/v, 5 mL) is added 3-methoxyphenylthiourea (99.6 mg, 0.272 mmol) and Na2CO3 (58 mg, 0.545 mmol). The reaction mixture is allowed to stir at 50° C. for 3 h. The reaction mixture is used directly in the next step: (M+H)+ 451.1.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[S:11][C:12]([CH2:14][CH3:15])=[CH:13][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:7][CH2:6][CH2:5]1)=[O:3].C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[C:9]2[CH:13]=[C:12]([CH2:14][CH3:15])[S:11][C:10]=2[N:4]([C:2]([N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:3])[CH2:5][CH2:6][N:7]=1
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1cc2c(s1)N(C(=O)N1CCN(C)CC1)CCN=C2c1ccccc1Cl
Product: Cl

Procedure:
To a solution of 12.0 g of 1-chlorocarbonyl-5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine and 3.8 g of triethylamine in 50 ml of toluene is added dropwise a solution of 3.8 g of N-methylpiperazine in 10 ml of toluene with stirring. The whole solution is refluxed with stirring for 30 minutes, and then cooled. The precipitated triethylamine hydrochloride is filtered off. After the filtrate is washed with water and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-(4-methyl-1-piperazinylcarbonyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloride 1/2 -hydrate as yellow crystals. This product, when recrystallized from acetone containing water, melts at 248°-250° C with decomposition.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46](OC)(OC)(OC)[O:47][CH3:48]>C(O)(=O)C>[CH3:46][O:47][C:48]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: COC(OC)(OC)OC
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Solvent: CC(=O)O
Product: COc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Reaction time: 72 h
Yield: 80.3 %

Procedure:
To a solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in acetic acid (1 ml) was added tetramethyl orthocarbonate (66 mg) at ambient temperature and the solution was allowed to stand at the same temperature for 3 days. After being concentrated in vacuo, the residue was diluted with chloroform and saturated sodium bicarbonate aqueous solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-methoxy-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (171 mg) as a powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[NH:8][N:7]=1.[C:14]([S:17][CH2:18][CH2:19][C:20](Cl)=[O:21])(=[O:16])[CH3:15]>C([O-])([O-])=O.[Na+].[Na+]>[C:14]([S:17][CH2:18][CH2:19][C:20]([N:8]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)=[O:21])(=[O:16])[CH3:15]
Reactant: O=C(O)C1CC(c2cccs2)=NN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)SCCC(=O)N1N=C(c2cccs2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(±)-4,5-Dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid is dissolved in aqueous Na2CO3 (1.38 g) at pH 8.6. The temperature is lowered to 5° C. and 3-(acetylthio)propionyl chloride (4.15 g) and a 25% solution of Na2CO3 are added simultaneously maintaining the pH at 8-9. The final pH is 8.9 and the reaction is stirred for 2 hours at room temperature. It is then extracted with ethyl acetate and the ethyl acetate is discarded. The aqueous layer is made strongly acid with 20% HCl and the gummy precipitate is extracted with ethyl acetate. The ethyl acetate is dried over MgSO4 and removed to yield a viscous residue (7.2 g) which is triturated with ether to yield 5.1 g of material, melting point 127°-130° C., dec. After recrystallization from CH3CN (very soluble) the melting point is constant at 134°-136° C., dec.