Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C1C=C(F)C(C#N)=C(F)C=1.[CH2:12]([OH:16])[CH2:13][CH2:14][OH:15].O.[C:18]1([CH3:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:20]1[CH:19]=[C:18]([CH:24]2[O:16][CH2:12][CH2:13][CH2:14][O:15]2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: OCCCO
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Brc1cccc(C2OCCCO2)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 100 %

Procedure:
A solution of 3-bromobenzaldehyde (1, 18.5 g, 100 mmol), propane-1,3-diol (9.1 g, 120 mmol) and p-toluenesulfonic acid monohydrate (0.1 g, 0.5 mmol) in toluene (200 mL) was refluxed with azeotropical removal of water using a Dean-Stark water separator for 15.5 h. The reaction mixture was cooled to room temperature, washed with 5% potassium carbonate solution (100 mL) and water (2×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (24.8 g, 100%): 1H NMR (500 MHz, CDCl3) δ 7.66 (t, J=1.8 Hz, 1H), 7.46 (ddd, J=7.9, 2.0, 1.1 Hz, 1H), 7.40 (br d, J=7.9 Hz, 1H), 7.23 (t, J=7.9 Hz, 1H), 5.46 (s, 1H), 4.28-4.25 (m, 2H), 4.00-3.95 (m, 2H), 2.26-2.17 (m, 1H), 1.47-1.43 (m, 1H); ESI MS m/z 243, 245 [M+H]+.
Reaction SMILES: O(C(C)(C)C)[K].Cl[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:11]=[CH:10][N:9]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>N1C=CC=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:13]2[C:8]([O:29][CH2:28][CH2:27][OH:30])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OCCO
Agent: CC(C)(C)O[K]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
KO-t-Bu (9.92 g, 103 mmol) was added to a mixture of the product obtained in Step 1 (18.14 g, 60.7 mmol) and ethylene glycol (25 mL, 448 mmol) in pyridine (125 mL) at 85° C. The reaction mixture was stirred for 15 h and then poured into ice-water and extracted with toluene. The organic phase was dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 16.9 g (85%) of the title product. HRMS m/z calcd for C15H24N4O4 (M)+324.1798, found 324.1784.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[CH:14][C:13]2=[O:26])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])=[CH:14][C:13]2=[O:26])[C:9]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.55 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (86 mg, 0.55 mmol) and 1-hydroxybenzotriazole (80 mg, 0.58 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 95 mg, 0.60 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (197 mg, 72%) as a white solid: LR-ES-MS m/z calculated for C26H32F2N4O4 [M]+ 502, observed [M+H]+ 503; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.35 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.48-1.85 (m, 7H) 3.89 (s, 2H) 4.26 (d, J=18.8 Hz, 1H) 4.64 (d, J=18.8 Hz, 1H) 4.68 (s, 1H) 4.90 (dd, J=10.7, 4.7 Hz, 1H) 5.03 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.20-7.50 (m, 3H) 7.53 (d, J=2.1 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[CH:8]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:22][CH2:23][CH2:24][N:25]=2)[CH:17]=[CH:18][C:19]=1[OH:20].[CH3:26][C:27]1ON=C(CCC(OC)=O)C=1>>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:22][CH2:23][CH2:24][N:25]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:26][CH2:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: Oc1ccc(C2=NCCO2)cc1Cl
Reactant: Cc1cc(CCCCCBr)on1
Reactant: COC(=O)CCc1cc(C)on1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{5-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole [IX; R=CH3, R1 =2-Cl, R2, R3, R4, R5 and R6 =H, Y=(CH2)5, oxazole at 4-position] was prepared from 5-(5-bromopentyl)-3-methylisoxazole and 4,5-dihydro-2-(3-chloro-4-hydroxyphenyl)oxazole (Example 13b) according to the procedure of Example 9, part (d), and was obtained in the form of a colorless solid, m.p. 102°-104° C. when recrystallized from isopropyl alcohol.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[C:35]([F:37])[CH:36]=1>C1(C)C=CC=CC=1.C1COCC1>[C:1]([S@@:5]([NH:7][C@H:8]([C:33]1[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=1)[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@]1(CC/C=N/[S@@](=O)C(C)(C)C)CCCN1C(=O)OCc1ccccc1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CC[C@H](N[S@@](=O)C(C)(C)C)c2cc(F)cc(F)c2)CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 1-benzyl 2-methyl (2R)-2-((3E)-3-{[(S)-tert-butylsulfinyl]imino}propyl)pyrrolidine-1,2-dicarboxylate from Step B (1.56 g, 3.70 mmol) in toluene (30 mL) at −78° C. was added 3,5-difluorophenylmagnesium bromide (14.8 mL of a 0.5 M solution in THF, 7.41 mmol) dropwise. The reaction mixture was stirred for 30 min at −78° C., 3.5 h at −10° C., and then at ambient temperature for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 0:100, to give the title compound. MS: m/z=537 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1[S:12](=[O:14])(=[O:13])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH:9]([NH:22][C:23](=O)[CH2:24][CH3:25])[CH2:8]1.CSC.B>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1[S:12](=[O:13])(=[O:14])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:17][C:10]=2[CH:9]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:8]1
Reactant: CCC(=O)NC1CC(COCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCCNC1CC(COCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 60 °C

Procedure:
To a solution of 11 (39.9 g, 0.021 mol) in THF (400 ml) under N2 was added dropwise 10M borane dimethylsulfide (42.5 ml, 0.42 mol). After addition, the reaction which was fitted with a short-path distillation head was heated to 60° C. for 3 h while collecting distilled dimethylsulfide and THF. The solution was then concentrated to dryness and then 6N HCl was carefully added dropwise. After addition the reaction was heated at reflux for 1/2 h, the solution was concentrated, flushed with EtOH (2×) and the residue was then carefully treated with saturated NaHCO3. The aqueous layer was extracted with EtOAc (4×) and the organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (120 mm) packed with silica gel and eluted with 20:1 CHCl3 --CH3OH to yield 15.4 g (40%) of trans -12 and then 4.7 g (12%) of cis-13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:16]([CH3:15])[NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CNN
Solvent: CCCCO
Product: CN(N)c1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A 10.0 g. portion of 6-(p-chlorophenyl)-3-chloropyridazine and 6.1 g. of methyl hydrazine in 125 ml. of butanol is mixed and heated at reflux overnight. The reaction mixture is cooled, filtered, the precipitate is washed with butanol and water and dried. Recrystallization from ethanol gives 6-(p-chlorophenyl)-3-(1-methylhydrazino)pyridazine.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[C:25]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:26][O:27][C:28]=2[C:29]([F:32])([F:31])[F:30])=[N:18][CH:17]=1.O>O1CCOCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][N:5]([C:15]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[C:25]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)=[N:26][O:27][C:28]=3[C:29]([F:30])([F:32])[F:31])=[CH:20][CH:21]=2)=[O:14])[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCNCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 504 μL, 1.0 mmol) was added dropwise (exothermic) to a solution of thiomorpholine-S,S-dioxide (136 mg, 1.0 mmol) in dioxane (7 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 days and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (32 mg, 25%) which was obtained as an off white solid. MS: m/e=500.0 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[O:20]1[CH2:22][CH:21]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1>CO.O>[ClH:1].[OH:20][CH:21]([CH2:22][NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:9][CH:10]=1)[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(OCC(O)CNCCOc2ccc(-n3ccnc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2.3 g (0.008 mol) of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanamine dihydrochloride in 100 ml of methanol add a solution of 0.66 g of sodium hydroxide in 5 mL of water. Stir for 15 minutes. Add 2.0 g (0.008 mol) of N-[4-(oxiranylmethoxy)phenyl]methanesulfonamide and reflux for 16 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride, methanol, triethylamine, 84:15:1). Remove the solvent in vacuo. Chromatograph the oil on 350 g of silica gel using amixture of methylene chloride:methanol:triethylamine (94:5:1). Combine the fractions containing residue and remove the solvent in vacuo. Dissolve theresidue in methanol and add a solution of hydrogen chloride in methanol. Remove the solvent in vacuo. Recrystallize the salt from acetonitrile:methanol to obtain the title compound.
Reaction SMILES: [C:1]([C:7]#N)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].S(=O)(=O)(O)[OH:10].CC(=C)C.[NH2:18][NH:19][C:20]([NH:22][NH2:23])=[S:21]>C(O)(=O)C.O>[NH2:18][N:19]1[C:7](=[O:10])[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:23][N:22]=[C:20]1[SH:21]
Reactant: NNC(=S)NN
Reactant: CC(C)(C)C(=O)C#N
Reactant: O=S(=O)(O)O
Agent: C=C(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Reaction time: 0.17 h
Yield: 93 %

Procedure:
111 grams (1 mole) of pivaloyl cyanide were dissolved in 200 ml of glacial acetic acid and treated at 0° to +5° C. with 152 grams (1.5 moles) of 97% sulfuric acid. Within 2 hours there were led in 112.2 grams (2 moles) of isobutylene at 0° to +5° C. In connection with the one hour post reaction at 20° C. there were added at the same temperature 200 ml of glacial acetic acid and 108 grams of water. The mixture was heated at boiling in a very slow current of nitrogen for 4 hours, whereby 92 grams (82% of that employed) of isobutylene escaped and was caught in a cooling trap. The mixture was treated at 80° C. with 100 grams of water and subsequently with 92.4 grams (0.87 mole) of thiocarbohydrazide. It was stirred for a further 10 minutes at 95° to 100° C. and then cooled. By filtration there were isolated 162 grams of the triazinone (I) having a melting point of 208°-210° C. (81% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 4-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (3:1). 0.59 g (87%) of 1-benzyl-piperidin-4-yl 4-fluoro-benzoate was obtained as a greenish oil.
Reaction SMILES: C(OC(=O)NCC[NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([NH:22][C:23]([C:25]1[NH:26][C:27]3[C:32]([CH:33]=1)=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=3)=[O:24])=[CH:17][CH:16]=2)=[O:12])(C)(C)C.[C:38](O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.Cl.[N:54]1([C:59]([NH2:61])=[NH:60])[CH:58]=[CH:57]C=N1>>[CH3:38][N:60]=[C:59]([NH2:61])[NH:54][CH2:58][CH2:57][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([NH:22][C:23]([C:25]1[NH:26][C:27]3[C:32]([CH:33]=1)=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=3)=[O:24])=[CH:17][CH:16]=2)=[O:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2cc(NC(=O)c3cc4cc([N+](=O)[O-])ccc4[nH]3)ccc2[nH]1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: COc1ccccc1
Product: CN=C(N)NCCNC(=O)c1cc2cc(NC(=O)c3cc4cc([N+](=O)[O-])ccc4[nH]3)ccc2[nH]1
Yield: 86 %

Procedure:
Compound 106 was treated with TFA/anisole according to the procedure for compound 41 and then reacted with 1H-pyrazole-1-carboxamidine hydrochloride according to the procedure for compound 47. Yield: 86%. MS: 449.15 (M+H+). 1H-NMR (DMSO-d6) 12.48 (s, 1H), 11.64 (s, 1H), 10.43 (s, 1H), 8.73–8.71 (m, 2H), 8.11–8.06 (m, 2H), 7.72–7.68 (m, 2H), 7.62–7.58 (d, 1H), 7.42–7.39 (m, 2H), 7.20–7.04 (m, 4H), 3.42 (t, 2H), 3.33–3.26 (m, 2H).
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]([OH:28])=O)=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[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.[CH3:78][N:79]([CH3:84])[CH2:80][CH2:81][CH2:82][NH2:83]>CN(C)C=O>[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]([NH:83][CH2:82][CH2:81][CH2:80][N:79]([CH3:84])[CH3:78])=[O:28])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCN
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
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: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 652.4 %

Procedure:
To a mixture of 0.125 g (0.257 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-trifluoromethyl-benzoic acid (I-204) and 9 mL of dimethylformamide was added 0.0521 g (0.386 mmole) of 1-hydroxybenzotriazole, 0.146 g (0.385 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.140 g (1.081 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0393 g (0.385 mmole) of 3-(dimethylamino)-propylamine 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, 95:5-80:20) gave 0.955 g 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)-N-(3-dimethylamino-propyl)-3-trifluoromethyl-benzamide (I-209) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:6][CH2:7]1
Reactant: CI
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1

Procedure:
To a solution of 2-(trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione (Glennon et al. J. Med. Chem. 1996, 39, 1, 314-322) (1.0 g, 40.77 mmol) in DMF (4.0 mL) was added NaH (60% in oil, 0.41 g, 10.2 mmol) followed by iodomethane (5.79 g, 40.7 mmol). The reaction mixture was stirred for 16 h before water (15 mL) and ethyl acetate (25 mL) was added and the phases were separated. The organic phase was washed with water (2×10 mL), dried over MgSO4 and the solvent was removed in cacuo. The residue was purified on silica gel (EtOAc-heptane) to give 0.810 g (77%) 2-(trans-4-methoxy-cyclohexyl)-isoindole-1,3-dione. 2-(trans-4-methoxy-cyclohexyl)-isoindole-1,3-dione (0.710 g, 2.74 mmol) in absolute ethanol (10 mL) was added hydrazine hydrate (0.130 g, 4.11 mmol) and the reaction mixture was stirred for 2 h at 50° C. The oilbath was removed and the mixture was stirred for 16 h at room temperature. The volatiles were removed in vacuo and the residue was added NaOH (20 mL, 10 N) and extracted with diethyl ether (3×10 mL). The organic phase was dried with MgSO4 and concentrated in vacuo to give 0.300 g (85%) of 4-trans-methoxy-cyclohexylamine. 4-Trans-methoxy-cyclohexylamine (100 mg, 0.78 mmol) and cyclopentanone (72 mg, 0.85 mmol) in THF-MeOH 2:1 (2 mL) and acetic acid (0.1 mL) was added sodium cyanoborohydride (73 mg, 1.02 mmol) in small portions over 15 min. The reaction mixture was stirred for 16 h before the volatiles were removed in vacuo. The residue was added HCl (1N, 50 mL) and stirred for 16 h at rt. The mixture was added NaOH (10N, 2.5 mL), extracted with diethyl ether (2×10 mL) and dried over MgSO4. The solvent was removed in vacuo to give 134 mg (88%) of cyclopentyl-(4-methoxy-cyclohexyl)-amine.
Reaction SMILES: N1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2N=CC=C3)C=CC=1.[C:15]([O-:18])([O-])=O.[Cs+].[Cs+].IC1C=[CH:26][C:25]([O:28]C)=[CH:24]C=1>[Cu]I.C(O)(C)C>[CH:25]([O:28][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH3:15])=[CH:13][CH:14]=1)([CH3:26])[CH3:24]
Reactant: COc1ccc(I)cc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1ccc(OC(C)C)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 415.1 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), Cs2CO3 (456 mg, 1.4 mmol), 4-iodoanisole (234 mg, 1.0 mmol) and isopropanol (1.0 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with ethyl acetate. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane/ethyl acetate 20:1) provided 138 mg (83% yield) of the title compound as a colorless oil.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[N:33]1([C:20]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: NS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 85 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-sulfamoyl-benzoic acid (CAS: 97-04-1; Basu; D.-G.; J.Indian Chem.Soc.; 16; 1939; 100, 106) and morpholine and obtained in 85% yield. MS (m/e): 285.1 (MH− 100%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13].NC1C=C(C=CC=1)CO.C(#N)CC#N.[OH2:30].[NH2:31][NH2:32]>>[NH2:13][C:12]1[C:11](=[N:10][NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][OH:30])[C:14]([NH2:15])=[N:32][N:31]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccccc1CO
Reactant: O
Agent: Nc1cccc(CO)c1
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccccc1CO

Procedure:
{2-[N′-(3,5-Diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol was prepared using 2-[(2-hydroxymethylphenyl)hydrazono]malononitrile (0.100 g, 0.5 mmol) which was derived from 3-aminobenzyl alcohol (0.123 g, 1.0 mmol) and malononitrile (1.5 mmol) in a manner similar to that described in Example 2, and hydrazine hydrate. The title compound was obtained as a brown solid (32 mg, yield 28%); 1H NMR (ppm, 200 MHz, DMSO-d6) δ 4.51 (d, 2H), 5.20 (t, 1H), 6.0 (br s, 4H), 7.15 (d, 1H), 7.30 (t, 1H), 7.45-7.60 (m, 2H), 10.60 (br s, 1H).