Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[C:24]([Cl:36])[CH:23]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:24]1[CH:23]=[C:22]([NH:21][C:13]2[C:12]3[C:11]4[CH2:10][CH2:9][NH:8][CH2:20][C:19]=4[S:18][C:17]=3[N:16]=[CH:15][N:14]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCNC4)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a 4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.6 g, 6.87 mmol) in DCM (45 mL) solution was added TFA (5.2 mL, 68.7 mmol, 10 equiv). The reaction mixture was stirred at rt for 8 h. The solution mixture was concentrated in vacuo. To the residue was added sat. NaHCO3 solution and stirred at rt for 1.5 h. The mixture was then filtered and washed with water. The damp solid was placed in a vacuum oven and dried for overnight to yield a yellow solid (2.0 g, 67%). 1H NMR (DMSO-d6) δ 9.41 (broad s, 2H), 8.71 (d, J=5.0 Hz, 1H), 8.40 (s, 1H), 8.11 (t, 1H), 7.75 (m, 2H), 7.57 (m, 1H), 7.53 (dd, J=2.7, 9.0 Hz, 1H), 7.25 (d, J=9.4 Hz, 1H), 5.35 (s, 2H), 4.48 (m, 2H), 3.49 (m, 2H), 3.41 (m, 2H); LCMS RT=2.11 min, [M+Na]+=446.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-:3])=[O:2].[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[C@H:16]1([NH:15][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[N:9]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=[N+]([O-])c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
5-Nitro-2-chloroquinoline (CAS 13067-94-2, 2.4 g, 11.5 mmol) and (R)-1-aminoindane (3.13 g, 23.5 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). (R)-Indan-1-yl-(5-nitro-quinolin-2-yl)-amine was obtained as a brown solid (2.67 g, 76%), MS: m/e=306.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12].[OH-].[K+].Cl>>[C:3]([OH:13])(=[O:2])[CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12]
Reactant: CC=CC=CCCC=CC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC=CC=CCCC=CC(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In an atmosphere of nitrogen, 2,6,8-decatrienoic acid methyl ester (6); 19.1 g {GC; 93.9%, pure amount; 17.9 g (0.0995 mol)} and 5 mol/l of potassium hydroxide aqueous solution (60 ml, 0.30 mol) were added to a 200 ml capacity flask, followed by stirring at 70° C. for 2 hours. After completion of the reaction, the reaction was stopped with 5 mol/l of hydrochloric acid (63 ml, 0.315 mol), and then extraction with toluene (32 ml) was carried out to obtain a toluene solution of 2,6,8-decatrienoic acid (7).
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:4]>CO>[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([O-:8])=[O:7])[CH3:4].[Na+:2]
Reactant: CCCCC(CC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(CC)C(=O)[O-]
Temperature: 185 °C
Reaction time: 18 h

Procedure:
A round bottom flask (250 mL) was charged with a stir bar, sodium hydroxide (13.87 g, 0.347 mol) and methanol (200 mL) under ambient conditions. 2-Ethylhexanoic acid (50.00 g, 0.347 mol) was added dropwise to the stirred solution over 30 min. The solvent was then removed by rotary evaporation producing a white, tacky solid. This white solid was then heated at 185° C. and a pressure less that 25 torr for 18 hr, yielding anhydrous sodium 2-ethylhexanoate as a hard, white solid (97% isolated yield). Anhydrous sodium 2-ethylhexanoate is very hygroscopic and was handled under an inert and substantiallydry atmosphere.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[N:7][N:8]=1.[I-].[K+].[F:17][CH2:18][F:19]>O.O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:17][CH:18]([F:19])[S:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[N:7][N:8]=1
Reactant: FCF
Reactant: Sc1nnc(-c2cnccn2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Sc1nnc(-c2cnccn2)s1
Yield: 4223.2 %

Procedure:
To a solution of 6.2 g of 85% potassium hydroxide in 18 ml of water is added a solution of 6 g (0.03 mol) of 2-mercapto-5-pyrazin-2-yl-1,3,4-thiadiazole in 90 ml of dioxane. Then 0.2 g of potassium iodide and 0.2 g of tetrabutylammonium bromide are added to the reaction mixture and 13 g of gaseous difluoromethane are introduced over 6 hours at 22° to 37° C. After evaporating off the dioxane, the reaction mixture is diluted with ethyl acetate, the aqueous phase is separated and the organic solution is washed cold with 1N sodium hydroxide solution and water, dried over sodium sulfate and clarified with activated carbon. The ethyl acetate is removed under vacuum and the residue is crystallised from ethyl acetate/hexane, affording 312 g (43%) of the title compound with a melting point of 113°-115° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]#[N:13])[CH:4]=[CH:3]1.CN1C2C(=CC=CC=2C=[O:25])C=C1.[Li]C#N.C(OP(C#N)(=O)OCC)C.C(O)(C)(C)C>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:13])=[O:25])[CH:4]=[CH:3]1
Reactant: Cn1ccc2cccc(CC#N)c21
Reactant: Cn1ccc2cccc(C=O)c21
Agent: CCOP(=O)(C#N)OCC
Agent: [Li]C#N
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cn1ccc2cccc(CC(N)=O)c21
Reaction time: 0.5 h

Procedure:
(1-Methyl-1H-indol-7-yl)-acetonitrile (adapted from the procedure described in YONEDA, R.; HARUSAWA, S.; KURIHARA, T. Tetrahedron Lett. 1989, 30, 3681–3684; YONEDA, R.; HARUSAWA, S.; KURIHARA, T. J. Org. Chem. 1991, 56, 1827–1832). A solution of 1-methyl-1H-indole-7-carboxaldehyde (137 mmol, crude material prepared as described above), LiCN 1.5 THF complex (1.94 g, 13.7 mmol), and diethylcyanophosphonate (27.1 mL, 179 mmol) in THF (400 mL) was stirred at room temperature overnight. Tert-butanol (13.1 mL, 137.7 mmol) was introduced and the mixture was transferred via cannula into a 0.1 M solution of SmI2 in THF (3.6 L, 360 mmol) and the mixture stirred for 30 minutes. The mixture was concentrated to dryness, the residue was taken up in EtOAc (2 L), and the solution was washed with 1N HCl (3×500 mL), saturated aq NaHCO3, and brine. The solution was dried (MgSO4), passed through a pad of silica gel, and concentrated to give the title compound in sufficient purity for use in the next step. Flash chromatography (90% hexane/EtOAc) can be used to afford the title compound pure, as an off-white crystalline solid. 1H (400 MHz, DMSO-d6) 7.51 (d, J=7.5 Hz, 1H), 7.28 (d, J=3 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.43 (d, J=3 Hz, 1H), 4.58 (s, 2H), 4.07 (s, 3H). 13C NMR (75.5 MHz, DMSO-d6) 133.56, 131.89, 130.06, 122.38, 120.74, 119.53, 119.16, 114.47, 100.59, 35.86, 20.43. IR (CHCl3, cm−1) 2252. MS (electrospray, m/z) 171 (M++1). Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C, 77.62; H, 5.96; N, 16.38.
Reaction SMILES: CN1CCOCC1.Cl[C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([S:15]([O:18][C:19]2[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=2)(=[O:17])=[O:16])[CH:14]=1>[Pd].CO>[CH3:28][O:27][C:12]1[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=1[S:15]([O:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=1)(=[O:16])=[O:17]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: [Pd]
Solvent: CO
Solvent: CN1CCOCC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
4-Methylmorpholine (3.2 mL, 29.1 mmol) was added to a mixture of 3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenol (8.82 g, 26.8 mmol, prepared in the preceding step) and 10% palladium on carbon(2.23 g) in deoxygenated methanol (15 mL). The mixture was stirred at ambient temperature under hydrogen (balloon) for 3 h, then filtered through Celite (drafomaceous earth) with methanol. Solvent was removed in vacuo and crude product was purified by flash column chromatography (CH2Cl2 to 5% ethyl acetate in dichloromethane) to give the title compound (4.97 g, 63%) as a colorless syrup. 1H-NMR (300 MHz, DMSO-d6) (9.71 (s, 1H), 7.76 (ddd, 1H, J=8.4, 7.4, 1.7 Hz), 7.69 (dd, 1H, J=7.9, 1.7 Hz), 7.38 (d, 1H, J=8.4 Hz), 7.09 (dt, 1H, J=7.9, 1.0 Hz), 6.48 (br s, 1H), 6.33 (br s, 1H), 6.26 (t, 1H, J=2.2 Hz), 4.00 (s, 3H), 2.15 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C14H14O5S: 317.0 (M+Na). Found: 316.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]1[S:13][C:14]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1)=[O:28]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1OC
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc([N+](=O)[O-])cc3s2)cc1OC

Procedure:
The title compound was synthesised from (3,4-Dimethoxy-phenyl)-(6-nitro-benzothiazol-2-yl)-amine and 2,4-dichlorobenzoyl chloride (commercially available) according to the procedure described for Example 2. MS (m/e): 504.1 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:20])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:5]2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH3:21][N:22]([CH3:26])[C:23]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:20])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:5]2)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: O=C(CCc1cccs1)N1CCc2cc(O)ccc2C1
Solvent: c1ccncc1
Product: CN(C)C(=O)Oc1ccc2c(c1)CCN(C(=O)CCc1cccs1)C2

Procedure:
To a solution of the product of Example 14 (1.5 g) in pyridine (10 mL) at 0° C. was added dropwise dimethyl carbamyl chloride (0.52 mL) and the resulting solution was heated at 70°-80° C. for 24 hours. The pyridine was removed and the reaction diluted with CH2Cl2, washed with water (3x), brine, dried (MgSO4), filtered and concentrated. Chromatography of the residue on silica gel (elution with 1% CH2OH/CH2Cl2) provided 1.29 g of the desired product.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(O)(C)C>[CH3:13][C:12]([O:11][C:1](=[O:10])[CH:2]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A suspension of di-tert butyl malonate (10.80 g, 50 mmol) and t-BuOK (5.60 g, 50 mmol) was stirred (30 min, 75° C.) in t-BuOH (150 mL, dried over 4 Å sieves). To this was added a solution of 1-bromotetradecane (13.85 g, 50 mmol) and the reaction stirred at 75° C. overnight. Solvent was removed by rotary evaporation, giving a white semi-solid, which was partitioned between CH2Cl2 (100 mL) and saturated aqueous NaCl (2×300 mL), dried (MgSO4) and evaporated to a colorless oil (15.3 g). Purification by silica gel flash chromatography (100% hexane incremented to hexane:CH2Cl2 (70:30)) gave product 34 as a colorless oil (10.0 g, 48%). High resolution FAB MS:C25H49O4 (M+H); Theor. 413.3630855. Found 413.3627625.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27][CH2:26]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[O:34])[CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]2=[O:18]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reactant: C=CC(=O)N1CCN(C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccc(C=CC(=O)N2CCN(C)CC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(5-bromo-2-n-propoxy-phenyl)-8-methylquinazolin-4(3H)-one (Preparation 11; 0.5 g, 0.0013 mol), 1-methyl-4-propenoylpiperazine (Makromol. Chem., 1984, 185, 1525; 0.24 g, 0.0015 mol), palladium diacetate (0.175 g, 0.00077 mol), tri-o-tolylphosphine (0.30 g, 0.001 mol), triethylamine (1 ml) and acetonitrile (25 ml) was heated under reflux under a nitrogen atmosphere for 4 days. The cool mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (25 ml), the resulting solution extracted with dichloromethane (50 ml) and the organic extract washed with brine (2×30 ml) dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (10 g), using a methanol in dichloromethane elution gradient (0-4%), gave the title compound which crystallized from hexane-ethyl acetate as a pale pink solid (0.072 g, 12%), m.p. 184-185° C.
Reaction SMILES: [CH2:1]1[C@@H:11]2[C@H:5]([CH:6]=[CH:7][C:8]3[C:9]4[N:10]2[C:12]2[CH:21]=[CH:20][N:19]=[CH:18][C:13]=2[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:30][CH:31]=[C:32]([Cl:34])[CH3:33].O>CN(C)C=O>[Cl:34][C:32]([CH3:33])=[CH:31][CH2:30][CH:3]1[CH2:4][CH:5]2[CH:6]=[CH:7][C:8]3[C:9]4[N:10]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH:11]2[CH2:1][CH2:2]1
Reactant: CC(Cl)=CCCl
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cl)=CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A suspension of 2.76 g of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3';2,3]indolo[1,7-ab][1]benzazepine in 20 ml of dimethylformamide (DMF) containing 2.3 ml triethylamine was treated with 1.25 g of 1,3-dichloro-2-butene. Solution resulted immediately. The solution was stirred at room temperature for 4 hours, by which time some white precipitate had formed. The reaction mixture was poured into 150 ml of cold water, a gummy solid was separated and washed by decantation with cold water. Recrystallization from ethanol gave 2.93 g of the title compound, m.p. 130°-132° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.Cl[C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][C:33]=2[C:34]#[N:35])=[CH:25][CH:26]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyl alcohol (4.00 g), 2-chloro-3-cyanopyridine (2.41 g) and N,N-dimethylformamide (80 mL) was gradually added sodium hydride (60%, oil, 700 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 2 hrs, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization from ethyl acetate-isopropyl ether gave colorless prism crystals (4.02 g, 78%) of 2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]nicotinonitrile. melting point: 145-146° C.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=2)[CH:6]=1
Reactant: CCCc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (96 mg, 192 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (438 mg, 296 μL, 3.84 mmol) and the mixture stirred at room temperature overnight. The mixture was concentrated in vacuo then diluted with 25% aqueous NH4OH and dichloromethane. The phases were separated and the organic phase washed with water. The organic layer was concentrated in vacuo then purified by chromatography (silica, 3 to 20% methanol in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (59 mg, 148 μmol, 77%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.36 (s, 1H), 8.30 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 3.96 (s, 1H), 3.79 (s, 3H), 3.28 (s, 1H), 2.72 (t, J=7.3 Hz, 2H), 1.54-1.74 (m, 8H), 1.35 (m, 2H), 0.94 (t, J=7.4 Hz, 3H); MS (EI/CI) m/z: 400.2 [M+H].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(Cl)Cl>[CH3:8][S:9]([O:13][CH2:14][C:15]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:16]=1[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:20]([C:21]#[N:22])[CH:19]=1)(=[O:11])=[O:10]
Reactant: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C(F)(F)F)cc1Oc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.33 ml) followed by methanesulphonyl chloride (0.185 ml) were added to a solution of the product from step (ii) (0.7 g) in DCM (20 ml) at −20° C. The mixture was stirred at 0° C. for 1 h, then diluted with dichloromethane, washed with water, dried and evaporated under reduced pressure, yield 0.97 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([C:23]2[CH:24]=[N:25][C:26](F)=[CH:27][CH:28]=2)[C:5]([O:21][CH3:22])=[C:6]([CH:8]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[C:12]([CH3:20])=[N:11]2)[CH3:9])[CH:7]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(O)CCC>[NH2:19][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:10]([CH:8]([C:6]3[C:5]([O:21][CH3:22])=[C:4]([C:23]4[CH:28]=[CH:27][C:26]([NH:34][CH2:33][CH2:31][OH:32])=[N:25][CH:24]=4)[C:3]([CH3:30])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:11]=[C:12]([CH3:20])[C:13]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(F)nc1
Reactant: NCCO
Solvent: CCCCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(NCCO)nc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 15 %

Procedure:
A mixture of 1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.023 mmol) and ethanolamine (0.10 mL) in 1-butanol (1 mL) was stirred at 130° C. for 5 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.6 mg, 15%). The product was isolated as a single enantiomer. LCMS calculated for C23H27ClN7O2 (M+H)+: m/z=468.2; Found: 468.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37].F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C>CN(C)C=O>[CH:20]([C:17]1[S:16][C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:41]([C:43]([F:45])([F:46])[F:44])=[CH:42][C:34]=3[O:33][CH3:32])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[N:19][N:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc(CCN)cc2)s1
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)ccc1C(=O)NCCc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
6.53 g 4-(2-Amino-ethyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzene sulfonamide hydrochloride were dissolved in 150 ml dimethylformamide. 8.54 ml N,N-diisopropylethylamine, 3.6 g 2-methoxy-4-(trifluoromethyl)benzoic acid and 6.44 g O-((Ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting residue was purified by RP-HPLC to obtain 5.0 g N-{2-[4-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-2-methoxy-4-trifluoromethyl-benzamide as white solid.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=O)[C:24]2=[O:32])=[CH:19][CH:18]=1.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=4)[N:14]=3)[C:24]2=[O:32])=[CH:19][CH:18]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1C(c2ccc(F)cc2)CCN1Cc1nc(-c2ccc(C(F)(F)F)nc2)no1
Temperature: 85 °C

Procedure:
(Z)—N-Hydroxy-6-(trifluoromethyl)nicotinimidamide (0.082 g, 0.399 mmol), 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.086 g, 0.363 mmol; Example 216A) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.104 g, 0.544 mmol) were stirred together in dichloroethane (1 mL) at room temperature for 4 hours. The reaction was heated to 85° C. and heated overnight. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes (Flow=36 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 9.41 (d, J=1.7, 1H), 8.58-8.50 (m, 1H), 7.84 (dd, J=0.5, 8.1, 1H), 7.33-7.26 (m, 2H), 7.11-7.01 (m, 2H), 4.98 (d, J=17.0, 1H), 4.87 (d, J=17.0, 1H), 3.78 (t, J=9.0, 1H), 3.74-3.61 (m, 2H), 2.67 (dddd, J=4.3, 7.0, 9.1, 13.2, 1H), 2.26 (ddd, J=8.5, 13.0, 16.5, 1H); MS (ESI+) m/z 407.0 (M+H)+.