Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1.[N:38]1([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CCOC(C)=O>[OH:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]3[CH:17]=[C:16]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]5[O:30][CH:31]=[CH:32][C:33]=5[CH3:34])=[O:28])[CH:21]=4)[CH:15]=[N:14][CH:13]=3)=[CH:5][CH:4]=2)[CH2:40][CH2:39]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CBr)cc3)c2)c1
Reactant: OCCOCCN1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CN4CCN(CCOCCO)CC4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude N-{[4-(Bromomethyl)phenyl] (methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide was dissolved in THF (2 mL). 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.064 g, 0.390 mmol) and TEA (0.054 mL, 0.390 mmol) were then added to the solution and the resulting reaction mixture was allowed to stir for 1 h at rt. The reaction mixture, subsequently, was dissolved in EtOAc and then extracted with H2O (2× mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to afford the title compound (0.064 g, 49% overall for step 1 and 2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([OH:14])=O)[S:8][C:6]=2[N:7]=1.[CH3:21][C:22]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([N:29]3[CH2:30][CH2:31][N:26]([C:22]([CH3:25])([CH3:21])[CH2:23][OH:24])[CH2:27][CH2:28]3)=[O:14])[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC(C)(CO)N1CCNCC1
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: CC(C)(CO)N1CCN(C(=O)Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 57.1 %

Procedure:
A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)acetic acid (80 mg, 0.25 mmol), 2-methyl-2-piperazin-1-ylpropan-1-ol (48 mg, 0.31 mmol), HATU (116 mg, 0.31 mmol) and DIPEA (133 μL, 0.76 mmol) in DMF (3 mL) was stirred at r.t. for 65 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (65 mg, 56%). LCMS (method H): RT 2.02 min [M+H]+ 455.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NC1CCCC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Yield: 92.2 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (2.65 g, 10.0 mmol) was treated with cyclopentylamine (1.06 g, 1.2 eq. 12.0 mmol) following a method similar to general procedure B to afford 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (2.9 g). The obtained amino-ester (0.5 mmol) was subjected to reaction with ethyl isocyanate (2.0 mmol) according to general procedure C to furnish 1-cyclopentyl-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (83 mg). LCMS: m/z 340 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 7.78 (d, 1H), 7.55 (t, 1H), 7.20 (d, 1H), 4.99 (p, 1H), 4.13 (s, 3H), 4.11 (q, 2H), 2.42 (m, 2H), 2.06 (m, 4H), 1.62 (m, 2H) and 1.32 (t, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:18](=[O:19])[CH2:17][O:16][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCNCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)COC(C)=O
Temperature: 20 °C

Procedure:
To a 0° C. solution of diethylamine (1819 mL) and triethylamine (25.5 mL) in 500 mL of methylene chloride was added dropwise, with stirring, 25 g of acetoxyacetyl chloride. The ice bath was removed, and the mixture allowed to warm to 20° C. while stirring for an additional 2 hr. After filtration to remove amine hydrochloride salts, the methylene chloride solution was evaporated under reduced pressure to provide 29.1 g of crude, N,N-diethylacetoxyacetamide, as a yellow oil. The yellow oil was dissolved in 125 mL of methanol and 168 mL of 1N sodium hydroxide added with stirring. A slight exotherm was noted, and the mixture was allowed to stir for 2 hr. without further warming. Solvents were removed under reduced pressure to 1/4 volume, and the remaining aqueous solution extracted with ethyl acetate (200 ml). The ethyl acetate extract was dried over anh. sodium sulfate, and evaporated under reduced pressure to provide 14.0 g of N,N-diethylglycolamide as a yellow oil.
Reaction SMILES: C([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[C:11]1[NH:15][N:16]=[CH:17][C:10]1=[CH:9][CH:8]=2)(O)=O>N1C2C(=CC=CC=2)C=CC=1C>[OH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[CH:17]=[N:16][NH:15][C:11]3=2)[N:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cnc2ccc3cn[nH]c3c2c1O
Agent: Cc1ccc2ccccc2n1
Product: Oc1ccnc2ccc3cn[nH]c3c12
Yield: 73.6 %

Procedure:
A mixture of 8-carboxy-9-hydroxy-1H-pyrazolo[3,4-f]quinoline (5.00 g, 21.8 mmol) and quinaldine (50 ml) were refluxed for 20 hours. After cooling, the precipitate was collected by filtration and washed thoroughly with ether to give 9-hydroxy-1H-pyrazolo[3,4-f]quinoline (2.97 g, 74%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]#[N:13].[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][C@@H:18]([NH2:27])[CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:27][C@H:18]([CH2:17][CH2:16][N:15]([CH3:14])[CH3:28])[CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)#[N:13]
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1C#N

Procedure:
The title compound was prepared from 4-fluoro-3-(cyano)benzenesulfonamide and (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine using the procedure described for Intermediate 4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH2:15](OS(C)(=O)=O)[C:16]#[C:17][CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:15]([O:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:16]#[C:17][CH3:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reactant: CC#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#CCOc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 12 h

Procedure:
2-nitro-4-trifluoromethyl-phenol 7 (4.1 g, 20 mmol) and methanesulfonic acid but-2-ynyl ester 20 (3.0 g, 20 mmol) are dissolved in MeCN. Cs2CO3 is added (13.0 g, 40 mmol) and the mixture is stirred at 90° C. for 12 hours. The mixture is then filtered, concentrated in vacuo, diluted with H2O and extracted three times with DCM. The organic layers are combined, dried (MgSO4), filtered, and concentrated and the remainder purified by column chromatography using a hexanes/EtOAc gradient to afford 1-but-2-ynyloxy-2-nitro-4-trifluoromethyl-benzene 21 as a yellow solid: 1H-NMR (400 MHz, CDCl3) δ=8.06 (d, J=1.7 Hz, 1H), 7.73 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 4.81 (q, J=2.3 Hz, 2H), 1.79 (t, J=2.3 Hz, 3H). MS calculated for C11H9F3NO3 (M+H+) 260.1, found 260.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1

Procedure:
U.S. Pat. No. 5,786,473 describes a reaction of 5-bromoindole with N-methyl-4-piperidone to obtain 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole which is condensed with N-methylvinylsulfonamide to afford N-methyl-2-[3-(1,2,3,6-tertahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulfonamide which is reduced under heterogeneous hydrogenation conditions to obtain naratritpan.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[CH2:28][CH2:29][OH:30]>C(OCCO)C>[OH:30][CH2:29][CH2:28][C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccccc1CCO
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccccc3CCO)c2cc1OC
Yield: 62.5 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 178.3 mg (1.3 mmol) of 2-aminophenethyl alcohol to give 218.4 mg (64.4%) of the product as a pink solid, m.p 159-162° C., mass (electrospray, m/e): M+H 349.9.
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].ClCl.C(O)C>CCCCCC.C(OCC)(=O)C>[C:20]([NH:24][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Agent: ClCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)Nc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.395 g, 0.0015 mol) and tert-butylamine (4 ml, 0.038 mol) in enough CH2 Cl2 to form a solution (a small amount of dry ethanol was required) was stirred at room temperature for two days. During this time, a precipitate forms. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The reaction is evaporated to a solid on a rotary evaporator. The solid is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-(tert-butylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.270 g (0.00095 mol, 62%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:19]
Reactant: CCOC(=O)CCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
4-Cyanophenol (5.0 g) is dissolved in DMF (40 ml), and thereto are added ethyl 5-bromopentanoate (11.4 g) and potassium carbonate (6.38 g), and the mixture is stirred at room temperature for 24 hours. The reaction mixture is poured into water, and the mixture is extracted three times with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, solvent; hexane/ethyl acetate=5:1 to 5:2). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (9.86 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[C:9]1([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH:16]=[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:19]=[N:18]2)=[N:3][CH:4]=1
Reactant: Fc1ccc(I)cn1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(-n2cc(-c3ccccc3)cn2)nc1
Temperature: 85 °C
Yield: 93.7 %

Procedure:
A mixture of 2-fluoro-5-iodopyridine (368.3 mg, 1.652 mmol), 4-phenyl-1H-pyrazole (238.2 mg, 1.652 mmol), and potassium carbonate (457 mg, 3.30 mmol) in N,N-dimethylformamide (3.30 mL) was heated to 85° C. for 21 hours. The reaction was then concentrated and the crude residue diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated to give 5-iodo-2-(4-phenyl-1H-pyrazol-1-yl)pyridine (537.2 mg, 94%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.76 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.7, 2.2 Hz, 1H), 8.01 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.55-7.61 (m, 2H), 7.36-7.43 (m, 2H), 7.25-7.31 (m, 1H). MS (M+1): 348.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[OH-:17].[Na+]>O1CCOCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:17])[N:7]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(COc2ccnc(Cl)n2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(OCc2ccc(Cl)cc2)cc[nH]1
Temperature: 0 °C
Yield: 5 %

Procedure:
To a stirred solution of 2-chloro-4-((4-chlorobenzyl)oxy)pyrimidine (2.8 g) in dioxane and water (1:4, 30 ml) was added NaOH (440 mg), and the mixture was heated at reflux for 3 h. The reaction mixture was then cooled to 0° C. and the product was precipitated out from the reaction medium. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound (130 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.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.ONC(=O)[C@@H](O)[C@@H](C([N:61]1[CH2:66][CH2:65][N:64]([C:67]2[CH:72]=[C:71](C(F)(F)F)[CH:70]=[CH:69][N:68]=2)[CH2:63][C@H:62]1[CH3:77])=O)CC(C)C>CN(C=O)C.O>[CH3:16][C:2]1([CH3:1])[O:3][C:4](=[O:15])[C@H:5]([C@@H:7]([C:8]([N:61]2[CH2:66][CH2:65][N:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=3)[CH2:63][C@H:62]2[CH3:77])=[O:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[O:6]1
Reactant: CC(C)C[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@H](O)C(=O)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 49 %

Procedure:
To a cold (0° C.) solution of (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid (prepared according to WO 94/0244 or similarly to Seebach et al., 1990, Org. Syntheses, Coll. Vol. III, p 153-159; 7; 755.0 mg; 3.28 mmol; 1.0 eq.) and DIEA (1.18 mL; 6.89 mmol; 2.1 eq.) in DMF (4 mL) was added HATU (1.37 g; 3.61 mmol; 1.1 eq.) and the resulting reaction mixture was stirred for 2 min at 0° C. (3R)-3-methyl-1-pyridin-2-ylpiperazine (Intermediate 3, 639.3 mg; 3.61 mmol; 1.1 eq.) was then added and the resulting reaction mixture was stirred for 14 h at RT. Water was added and the mixture was extracted with Et2O (3×). The combined organic layers were washed with an aqueous saturated solution of NaCl, dried over MgSO4, filtered and evaporated to give an oil. This residue was purified by chromatography (gradient from 33% EtOAc in c-hex up to 50% EtOAc in c-hex in about 30 min) to give the title product as a white solid (625 mg, 49%) as a mixture of 2 diastereoisomers (HPLC (Condition D): Rt major: 13.7 min; Rt minor: 13.8 min.; major/minor: 55/45). M+(ESI): 390.3. HPLC (Condition A), Rt: 2.3 min (HPLC purity: 97.4%).
Reaction SMILES: [NH2:1][C:2]1([NH2:23])[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:8]=2)[NH:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[C:24]([NH:23][C:2]1([NH2:1])[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:8]=2)[NH:3]1)(=[O:26])[CH3:25]
Reactant: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(N)N3)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(NC(C)=O)N3)cc1OC
Yield: 77 %

Procedure:
A suspension of the compound of example 101 (10.46 g, 35 mmoles) in acetic anhydride (600 ml) and acetic acid (200 ml) was refluxed for 1 hour until a clear solution was formed. By cooling down the reaction mixture in the refrigerator, the precipitate formed was filtered off, washed with ethyl acetate and diethyl ether, and then dried over P2O5 under vacuum, providing the title compound as a yellow powder (9.19 g, yield: 77%). This compound was further characterized by the following spectra:
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(C)C>[C:10](/[N:9]=[C:8](\[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)/[NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][CH2:25][CH2:24][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:28][CH:29]=1)#[N:11]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Solvent: CC(C)O
Product: N#C/N=C(/Nc1ccc(OCCN2CCCC2)cc1)Oc1ccccc1

Procedure:
Diphenylcyanocarbonimidate (1.1 equiv) and 4-(2-(pyrrolidin-1-yl)ethoxy)aniline (1 equiv) were stirred in iso-propyl alcohol at ambient temperature overnight. The resulting white precipitate was filtered and washed with iso-propyl alcohol and dried to yield (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate. 3-Hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (82 mg, 0.36 mMol) and (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate (128 mg, 0.36 mMol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). The precipitate which formed in the microwave vial was re-dissolved in hot isopropanol. The mixture was cooled to ambient temperature and then filtered to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #1, as a yellow solid, 23 mg. 1H NMR (CDCl3, 300 MHz) 7.90 (s, 1H), 7.83 (t, 1H), 7.43 (m, 3H), 7.29 (t, 1H), 6.93 (d, 1H), 6.83 (br s, 2H), 6.39 (s, 1H), 4.17 (m, 2H), 2.98 (m, 2H), 2.60-2.80 (m, 8H), 2.32 (m, 2H), 1.87 (m, 4H) ppm; MS (ES) 483.16 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH:17][CH3:18])=[O:16].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O.[I-].[K+]>[CH3:18][NH:17][C:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: CNC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1CC(=O)NC
Reaction time: 16 h
Yield: 103 %

Procedure:
Potassium carbonate (2.81 g, 20.34 mmol) was given to a solution of 2-(2-hydroxyphenyl)-N-methylacetamide (3.36 g, 20.34 mmol) in acetone (150 ml). Ethyl bromoacetate (2.13 ml, 19.32 mmol) and potassium iodide (166 mg, 1.02 mmol) were added successively. The reaction mixture was heated to reflux for 6 h. It was left at room temperature for 16 h. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/dichloromethane (1:1) as eluent, to give 5.00 g of ethyl 2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[C:11]([F:28])([F:27])[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]3)=[CH:4][CH:3]=1>Cl.COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]4)=[N:9][N:8]=2)[N:7]=1
Reactant: COCCOc1cnc2ccc(C(F)(F)C(=O)NNc3ccc(Cl)nn3)cc2c1
Agent: Cl
Solvent: COCCOC
Product: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(Cl)nn34)cc2c1
Temperature: 130 °C
Yield: 56.2 %

Procedure:
A sealable microwave vial was charged with N′-(6-chloropyridazin-3-yl)-2,2-difluoro-2-(3-(2-methoxyethoxy)quinolin-6-yl)acetohydrazide (46.98 mg, 111 μmol), 1,2-dimethoxyethane (1.5 mL), and 1 drop of conc. HCl. The vial was sealed and heated at 130° C. for 40 min. The solution was concentrated and purified by MPLC (Teledine Isco combiFlash Companion). The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (12 g) using 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH to afford 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline (25.3 mg, 56.2%/yield) as a colorless solid. LRMS (ESI) m/z calcd for C18H15ClF2N5O2 (M+H) 406.1. found 406.2.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:14]=3[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.CCOCC.[NH4+].[Cl-]>O.O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:16]2([OH:20])[C:14]3[N:15]=[C:11]([C:10]4[C:2]([CH3:1])=[N:3][N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=45)[S:12][C:13]=3[CH2:19][CH2:18][CH2:17]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 250 mL round bottomed flask was placed 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6,7-dihydro-1,3-benzothiazol-4(5H)-one (505.1 mg, 1.783 mmol) and tetrahydrofuran (50 mL). To the mixture was added a solution of 4-chlorophenylmagnesium bromide in ether (1M, 3.0 mL, 3.0 mmol) and the mixture was stirred for 4 hr at rt. To the mixture were added a saturated aqueous solution of NH4Cl (50 mL) and water (50 mL) and the resulting mixture was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain crude 4-(4-chlorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4,5,6,7-tetrahydro-1,3-benzothiazol-4-ol as a yellowish off-white crystalline solid which was used in the next step without further purification.