Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C)C=CC(C1N(C2CCC2)C(C)=NC=1)=O.[S:18]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:49]=[CH:48][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:46])[CH3:45])[C:42]([CH3:47])=[N:41][CH:40]=4)[CH:36]=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])(=[O:20])=[O:19]>COCCO>[S:18]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:49]=[CH:48][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]5[CH2:46][CH2:1][CH2:45]5)[C:42]([CH3:47])=[N:41][CH:40]=4)[CH:36]=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])(=[O:19])=[O:20]
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)n1C(C)C
Solvent: COCCO
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)n1C1CCC1
Temperature: 110 °C

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-cyclobutyl-2-methylimidazole (Method 37 of WO 03/076435; 233 mg 1 mmol) and N-{4-[4-(methylsulphonyl)piperazin-1-yl]phenyl}guanidine (Method 1; 390 mg 1.3 mmol) in 2-methoxyethanol (8 ml) was stirred and heated for 18 hours at 110° C. The reaction mixture was evaporated under reduced pressure and the residue purified by chromatography on silica gel with MeOH:DCM (3:97 to 8:92). After evaporation and trituration with ether, the title compound was obtained as a yellow solid. (227 mg 48.5%). NMR: 1.60-1.71 (2×m, 2H), 2.36 (m, 4H), 2.49 (s, 3H), 2.91 (s, 3H), 3.18 (m, 4H), 3.25 (m, 4H), 5.51 (quintet, 1H), 6.91 (d, 1H), 6.97 (d, 2H), 7.30 (s, 1H), 7.54 (d, 2H), 8.33 (d, 1H), 9.23 (s, 1H); m/z 468.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(Cl)(Cl)Cl.CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Brc1ccccn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1ccc(NCCCOc2cccc(CN3CCCCC3)c2)nc1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (20 g) and 2-bromopyridine (12.64 g) were stirred at 125° C. for 31/2 days. The cooled reaction mixture was subjected to column chromatography on silica ((chloroform:methanol 10:1) to afford the title compound as an oil. This was treated with maleic acid in ethanol to give, on addition of diethyl ether, as a white solid 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]pyridine dimaleate (11.40 g), m.p. 116°-167° C. (recrystallised from isopropanol).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8](Cl)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C.CCOC(C)=O>[CH2:10]([O:9][CH2:8][N:1]1[CH:5]=[N:4][N:3]=[N:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCOCc1ccccc1
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COCn2cnnn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
To a mixture of tetrazole (500 mg, 7.13 mmol) in 14 mL DMF at 0° C. was added NaH (60%, 286 mg, 7.13 mmol). The mixture was stirred at 0° C. for 20 min, then was treated with BOM-Cl (80%, 1.35 mL, 7.84 mmol). The mixture was stirred at rt for 2 h, then was diluted with EtOAc. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 1″ SiO2 and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 483 mg of Intermediate 12.1 as a colorless oil.
Reaction SMILES: [C:1](/[CH:3]=[C:4](\[O-])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[Na+].Cl.[NH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14]>C(Cl)(Cl)Cl.C(OCC)C>[NH2:2][C:1]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:14]=1
Reactant: CCOC(=O)/C([O-])=C/C#N
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(N)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.5 %

Procedure:
To a suspension of sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (1.44 g, 8.78 mmol) in CHCl3 (80 mL) was added HCl (5 mL) in ethyl ether. t-butyl hydrazinecarboxylate (1.16 g, 8.78 mmol) was added, the mixture was stirred for 24 h at rt, the precipitate was removed by filtration, and the filtrate was concentrated to give 1-tert-butyl 5-ethyl 3-amino-1H-pyrazole-1,5-dicarboxylate (1.2 g, 37%), which was purified by preparative TLC. 1H NMR: δ 1.34 (m, 3H), 1.66 (s, 9H), 4.36 (m, 2H), 5.84 (s, 1H),
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Si:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:16])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:18]
Reactant: Cc1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Yield: 92.3 %

Procedure:
A mixture of the product from step 1 (3.9 g, 14.6 mmol) and 10% Pd—C (0.5 g, 50% wet) in ethyl acetate was hydrogenated under 50 psi hydrogen for 18 h. The mixture was filtered through Celite and the filtrate was evaporated, providing 3.2 g of 4-(tert-butyldimethylsilyloxy)-3-methylaniline, in 93% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:11][CH:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9]2)[CH:3]=1.[CH:16]([Si:19]([C:26]#[CH:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].C(N(CC)CC)C>[Cu](I)I.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>[CH3:15][O:14][CH2:13][CH2:12][CH:10]1[CH2:11][CH:8]([C:4]2[CH:3]=[C:2]([C:27]#[C:26][Si:19]([CH:16]([CH3:18])[CH3:17])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=[CH:6][CH:5]=2)[CH2:9]1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: COCCC1CC(c2cccc(Br)c2)C1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCCC1CC(c2cccc(C#C[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Yield: 90.3 %

Procedure:
In a CEM snap top microwave vial were combined 1-Bromo-3-[3-(2-methoxy-ethyl)-cyclobutyl]-benzene (0.340 gm 1.28 mmol), triisopropylsilylacetylene (0.29 g, 1.12 mmol), copper iodide (9 mg, 0.178 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.088 mmol) and triethylamine (1.30 g, 12.8 mmol). The vial was quickly agitated then irradiated in a CEM Explorer™ microwave instrument for 30 minutes at 80° C. Purification by column chromatography (hexanes) afforded an oil 375 mg (80%). This material was used in next step without further characterization.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Cl-].C[N+]1C=CN([C:48]([O:50][CH2:51][C:52]2[C:61]([N+:62]([O-:64])=[O:63])=[CH:60][C:57]([O:58][CH3:59])=[C:54]([O:55][CH3:56])[CH:53]=2)=[O:49])C=1>ClCCl.N1C=CC=CC=1>[N+:62]([C:61]1[C:52]([CH2:51][O:50][C:48]([O:38][C@@H:25]2[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26]2)=[O:49])=[CH:53][C:54]([O:55][CH3:56])=[C:57]([O:58][CH3:59])[CH:60]=1)([O-:64])=[O:63]
Reactant: COc1cc(COC(=O)n2cc[n+](C)c2)c([N+](=O)[O-])cc1OC
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(COC(=O)O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2CO)c([N+](=O)[O-])cc1OC
Temperature: 4 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 1.97 g 5′-O-(4,4′-dimethoxytrityl)thymidine (3.62 mmol) in 18 ml absolute dichloromethane and 2 ml absolute pyridine is added in a nitrogen atomsphere and in the absence of light to an N-methyl-N3-[(6-nitroveratryl)oxycarbonyl]imidazoliumchloride acylation reaction (19) (produced from 7.25 mmol chloroformic acid-6-nitroveratryl ester). The reaction mixture is stirred in the dark at 4° C. overnight. The molecular sieve is separated and the organic phase is extracted twice against saturated NaHCO3 (100 ml). After drying via Na2SO4, 200 ml of a 10% trichloroacetic acid in dichloroethane are added to the organic phase and stirred at room temperature for 5 minutes. The deep-red solution is extracted twice with saturated NaHCO3 (200 ml), the organic phase is dried via Na2SO4 and evaporated. Purification via flash chromatography (66-80% ethyl acetate in toluene) yielded 1.153 g of the title compound (66% yield)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br>C(#N)C>[CH2:4]([CH:3]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH2:2][N:1]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCC(Cc1ccccc1)c1cccc(O)c1
Reactant: BrCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Oc1cccc(C(Cc2ccccc2)CN2CCCC2)c1

Procedure:
To 3-(1-amino-3-phenylpropan-2-yl)phenol (0.6 g, 2.6 mmol) dissolved in 40 ml acetonitrile was added triethylamine (0.81 ml, 5.8 mmol) followed by 1,4-dibromobutane (0.37 ml, 3.2 mmol). The mixture was heated to reflux for 3 h then poured on ice-water and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and the solvent evaporated to obtain a yellow oil. m=665 mg (90%)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[O:24](S(C1C=CC(C)=CC=1)(=O)=O)[S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=O)=[O:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:13][C@H:14]([CH2:16][O:17][S:25]([C:28]4[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=4)(=[O:26])=[O:24])[CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](n3cc(I)c4c(N)ncnc43)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into the suspension of cis-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (1322 mg, 3.842 mmol) in CH2Cl2 (55 mL) was added dropwise pyridine (6749 μL, 21.7 eq.) at −78° C. under N2 over 10 min followed by the addition of a solution of Ts2O (1568 mg, 1.25 eq.) in CH2Cl2 (35 mL) over 20 min. After stirring at rt for 3 h, the reaction mixture was treated with saturated NaHCO3, and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (50 mL). The combined organic phases were washed with H2O (2×100 mL) and brine (100 mL), and dried over MgSO4. After removing the solvent, a brown paste (2050 mg) was obtained. The brown paste was purified by chromatography on silica gel (50 g pre-packed column) and eluted with CH2Cl2 (600 mL), 2% MeOH/CH2Cl2 (600 mL), and 4% MeOH/CH2Cl2 (600 mL) to obtain the title compound as a light-brown foam. 1H NMR (CDCl3, 400 MHz): δ=2.20-2.28 (m, 2 H), 2.47 (s, 3H), 2.47-2.52 (m, 1H), 2.57-2.64 (m, 2H), 4.12-4.13 (d, 2H, J=5.2 Hz), 5.07-5.11 (m, 1H), 5.63 (brs, 2H), 7.14 (s, 1H), 7.37-7.39 (d, 2H, J=7.6 Hz), 7.81-7.84 (m, 2H), 8.22 (s, 1H). MS (ES+): m/z 498.9 (100) [MH+]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([O:22]C)=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To methyl 5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (for a preparation, see Intermediate 54) (550 mg, 1.62 mmol) in MeOH (5 mL) was added lithium hydroxide monohydrate (78 mg, 3.24 mmol) in water (5 mL) and the mixture stirred at room temperature for 90 mins. The mixture was concentrated in vacuo before DCM was added. The mixture was filtered, dried by passing through a hydrophobic frit, and concentrated in vacuo to give 5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (517 mg, 1.59 mmol, 98% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10]N)[CH:7]=[CH:8][CH:9]=1.[C:12]1(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C.C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:13]3[CH2:12][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:10][C:6]=2[CH:5]=1
Reactant: O=C1CCc2ccccc21
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c3c([nH]c2c1)-c1ccccc1C3
Temperature: 85 °C
Yield: 52.2 %

Procedure:
To a solution of 3-methoxyphenylhydrazine hydrochloride (3.65 g, 20.9 mmol) and 1-indanone (2.77 g, 21.0 mmol) in ethanol (11.8 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Orange precipitate began to form upon cooling, and the mixture was subsequently emerged in an ice water bath to further induce crystallization. The solid was collected by vacuum filtration and dissolved in 22 mL isopropanol. Sulfuric acid (36 N, 1.5 mL) was added via syringe, and the resulting solution was stirred at reflux (90° C.) for 16 hours. Upon cooling to room temperature, the solution was basified to pH 10 with aqueous sodium hydroxide (2% by mass) resulting in the formation of precipitate. The solid was collected by vacuum filtration to yield 29a as an orange solid (2.55 g, 10.9 mmol). Crude product was brought on to the next step without purification. For purposes of characterization, the product was purified by flash column chromatography (20:1 hexanes-ethyl acetate). 1H NMR (600 MHz, CDCl3): δ 8.18 (s, 1H), 7.50-7.52 (m, 2H), 7.40-7.41 (d, 1H, J=7.2 Hz), 7.30-7.32 (t, 1H, J=7.8 Hz), 7.16-7.19 (td, 1H, J=7.8, 1.2 Hz), 6.95 (d, 1H, J=2.4 Hz), 6.83-6.84 (dd, 1H, J=8.4, 2.4 Hz), 3.88 (s, 3H), 3.69 (s, 2H); 13C NMR (150 MHz, CDCl3): δ 156.2, 147.3, 142.3, 141.5, 135.3, 126.5, 125.3, 124.1, 121.9, 119.5, 119.4, 116.7, 109.6, 96.2, 55.7, 30.3. FTIR: cm−1 3399, 1612, 1405, 1255, 1155, 1041, 820. ESI-HRMS: Calcd. for C16H13NO+ [M]+: 235.0992, found 235.0990.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH:13]1([NH:16][C:17]2[C:18]([NH2:25])=[CH:19][C:20]([F:24])=[C:21]([F:23])[CH:22]=2)[CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[CH:13]1([N:16]2[C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[NH:25][C:1]2=[O:2])[CH2:15][CH2:14]1
Reactant: Nc1cc(F)c(F)cc1NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(F)c(F)cc2n1C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.5 %

Procedure:
Carbonyldiimidazole (4.3 g) was added to the solution of N1-cyclopropyl-4,5-difluorobenzene-1,2-diamine (3.2 g) in THF (30 ml). The mixture was stirred at rt for 20 hours, then diluted with ethyl acetate (200 ml) and washed with hydrochloric acid (1M, 200 ml). Organic layer dried over sodium sulphate, solvent removed to give expected product as a black solid (2.5 g). 1H NMR (CD3OD)δ: 7.20 (dd, 1H), 6.95 (dd, 1H), 2.86 (m, 1H), 1.11 (m, 2H), 0.94 (m, 2H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.CCOCC>[C:5]1([C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]=[C:1]=[O:2])[CH2:15][CH2:16]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C=N[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 80 °C

Procedure:
Phosgene (20% in toluene, 5 ml) was added to a solution of trans-4-phenylcyclohexylamine (500 mg, 2.85 mmol) in toluene (5 ml) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 24 hours. Solvents were then removed under vacuum to leave a solid residue. This residue was dispersed in ether and filtered. The eluent was collected and concentrated to give 379 mg of trans-4-phenylcyclohexylisocyanate as a light yellow oil. IR (film) 2259 cm−1.
Reaction SMILES: [OH-].[Na+].O.[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]=1[OH:18])([CH3:7])([CH3:6])[CH3:5].[CH2:19](Br)[CH:20]=[CH2:21]>C1(C)C=CC=CC=1>[C:14]([C:10]1[CH:11]=[C:12]([CH2:21][CH:20]=[CH2:19])[CH:13]=[C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[C:9]=1[OH:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A 1 liter, 3 neck flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, dropping funnel and condenser was charged with 40 grams (1.0 mole) of sodium hydroxide and 50 ml. of H2O. The NaOH was dissolved with stirring and the solution was cooled to 25° C. and then 100 ml. of toluene, 2.06 grams (0.01 moles) 2,6-di-t-butyl phenol and 6.25 grams (≈0.006 moles) of S-X1 polystyrene quaternary phosphonium resin catalyst was charged into the reaction vessel. The dropping funnel was charged with a solution prepared from 49.44 grams (0.264 mole) of 2,6-di-t-butyl phenol, 32.0 grams (0.264 mole) of allyl bromide and 100 ml. of toluene. This solution was then added dropwise over a 40 minute period to the reaction vessel which had been heated to 50°-60° C. as stirring took place under a nitrogen blanket. After 3 hours of reaction time at 72° C. gas chromatographic analysis indicated that 50% of the starting materials had reacted to form 2,6-di-t-butyl-4-allyl phenol.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][S:40][CH2:41][CH2:42][NH:43][C:44](SC)=[CH:45][N+:46]([O-:48])=[O:47]>C(OCC)(=O)C>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:44]([NH:43][CH2:42][CH2:41][S:40][CH2:39][C:35]2[O:34][CH:38]=[CH:37][CH:36]=2)=[CH:45][N+:46]([O-:48])=[O:47])=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCN)o1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccco1
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCNC(=C[N+](=O)[O-])NCCSCc2ccco2)o1
Yield: 69.8 %

Procedure:
A mixture of N-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine (0.8 g.) and N-2-[[(2-furanyl)methyl]thio]ethyl-1-(methylthio)-2-nitroethenamine (0.57 g.) in ethyl acetate (8 ml.) was evaporated and the residue heated at 98°-100° for 2 hours. The oily residue was dissolved in methanol (10 ml.) and evaporated to dryness (×2). The oily residue was triturated with ethyl acetate (30 ml.), the solid which separated was washed with ethyl acetate and dried to give the title compound (0.82 g.), m.p. 69°-72°.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>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>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:31]=3)[CH2:14][CH:13]=[CH:12][N:11]2[CH3:16])[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: Cn1c(I)ccc1CC[C@]1(C)COC(=O)N1
Reactant: CC1(C)OB(c2cccc(OCCC3CCCCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CN1C=CCC1(CC[C@]1(C)COC(=O)N1)c1cccc(OCCC2CCCCC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.8 %

Procedure:
(4R)-4-Methyl-4-[2-(5-iodo-1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (0.3101 g, 0.92 mmol) obtained in Example (40a), 2-[3-(2-cyclohexylethyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4646 g, 1.41 mmol), dichlorobis(triphenylphosphine)palladium(II) (63.1 mg, 0.09 mmol) and cesium carbonate (0.6006 g, 1.81 mmol) were suspended in a mixed solvent of dimethoxyethane (8 ml) and water (2 ml) and stirred at 80° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the crude product. Furthermore, the crude product thus obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (41.1 mg, yield: 11%).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][NH2:23]>CO.C(O)(=O)C>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][N:23]=[C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: Cn1c(NN)nc2ccccc21
Reactant: COc1cccnc1C(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccnc1C(C)=NNc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl-3-methoxypyridine (0.50 g, 3.31 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.54 g, 3.31 mmol) in 10 ml of methanol is stirred at room temperature for 3 days after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of 20 ml of methanol and 10 ml of water. Yield: 0.87 g (89% of theory).