Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([C:31]([F:34])([F:33])[F:32])[CH:6]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>ClCCl.O>[F:36][C:2]([F:1])([F:35])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[C:7]([C:31]([F:32])([F:33])[F:34])[CH:6]=1
Reactant: FC(F)(F)COc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(F)(F)F)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1ccc(S)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
4-(2,2,2-Trifluoro-ethoxy)-2-trifluoromethyl-1-tritylsulfanyl-benzene (100 g, 193 mmol) was dissolved in dichloromethane (600 mL) and trifluoroacetic acid (44.9 g, 386 mmol) was added at room temperature, followed by a solution of triethylsilane (24.9 g, 214 mmol) in dichloromethane (75 mL) at 18° C. (ice bath cooling). The yellow mixture was stirred for 3 h at room temperature. Water (600 mL) was then added and dichloromethane was distilled off in vacuo under vigorous stirring. Tert-butyl-methylether (600 mL) was added and the resulting biphasic mixture was basified by addition of a concentrated aqueous sodium hydroxide solution (32% m/m, 54 mL, 583 mmol) to pH 12. Phases were separated, the aqueous layer was extracted with tert-butyl-methylether (400 mL), acidified by addition of hydrochloric acid (25% m/m in water, 35 mL, 268 mmol) to pH 3, and extracted with tert-butyl-methylether (600 mL). The organic extract was washed with a solution of sodium hydrogencarbonate (16.1 g, 193 mmol) in water (500 mL), and water (500 mL) and concentrated in vacuo to afford the title compound as a light yellow liquid (49.7 g, 90%). MS (ESI & APCI, neg): m/z=275.0 [M−H]+. 1H NMR (CDCl3, 600 MHz): δ3.66 (q, J=2.5 Hz, 1H), 4.36 (q, J=8.0 Hz, 2H), 6.99 (dd, J=2.9 Hz, 8.6 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H).
Reaction SMILES: FC(F)C1N2N=C(N3CCNCC3)C=CC2=NN=1.[F:19][CH:20]([F:48])[C:21]1[CH:22]=[C:23]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([C:37]([C:40](F)([F:42])[F:41])=[N:38][N:39]=3)[N:36]=2)[CH2:27][CH2:26]1>>[F:42][CH:40]([F:41])[C:37]1[N:35]2[N:36]=[C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH2:24][C:23]4[CH:44]=[C:45]([F:47])[CH:46]=[C:21]([CH:20]([F:19])[F:48])[CH:22]=4)[CH2:30][CH2:29]3)[CH:32]=[CH:33][C:34]2=[N:39][N:38]=1
Reactant: Fc1cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc(C(F)F)c1
Agent: FC(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1cc(CN2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)cc(C(F)F)c1
Yield: 66 %

Procedure:
Obtained in 66% yield by General Synthetic Method 5, starting from 3-(difluoromethyl)-6-(piperazin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Examples 248-263, preparation of starting materials) and 3-difluoromethyl-5-fluorobenzaldehyde (obtained as described in Example 783, preparation of starting materials).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14](OCC)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3.[BH4-].[Li+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH2:14][OH:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)c1cn2c(cnc3ccccc32)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: OCc1cn2c(cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.4 %

Procedure:
A solution of 7.2 g of ethyl imidazo-[1,2-a]-quinoxaline-2-carboxylate in 140 ml of anhydrous tetrahydrofuran and 1.0 g of lithium borohydride was refluxed with stirring for 20 hours and was then cooled to room temperature. 2 N hydrochloric acid was added dropwise to the mixture until effervescence ceased and the clear solution was stirred for one hour and made alkaline with saturated sodium bicarbonate solution. The mixture was concentrated under reduced pressure to evaporate the tetrahydrofuran and the mixture was poured into 500 ml of water. The mixture was cooled in an ice bath and filtered to obtain 4.9 g of imidazo-[1,2-a]-quinoxaline-2-methanol in the form of a colorless solid. The filtrate was extracted with chloroform and the organic phase was dried over magnesium sulfate and evaporated to dryness to obtain an additional 0.60 g of the desired compound in the form of needles melting at 158°-159° C. after crystallization from an ether-ethyl acetate mixture.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[C:5]2[C:17](=[O:33])[N:18]([CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[C:19](=O)[C:4]2=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[C:5]2[C:17](=[O:33])[N:18]([CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[C:19](=[S:43])[C:4]2=[CH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc2c(c(N3CCS(=O)(=O)CC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Solvent: Cc1ccccc1
Product: Cn1cc2c(c(N3CCS(=O)(=O)CC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Temperature: 120 °C
Reaction time: 16 h
Yield: 120.9 %

Procedure:
A suspension of 5-methyl-7-(1,1-dioxo-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (0.8 g, 1.715 mmol, see Example 3) in toluene (30 ml) was heated to 120° C., Lawesson's reagent (0.347 g, 0.857 mmol) was added and the reaction was stirred at 120° C. for 16 h. The solvent was removed and the resulting mixture was purified on a silica column (DCM/MeOH=50:1) to afford the title compound (0.5 g, 60% yield).
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([C:9](O)=[O:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH-].[Na+]>O>[C:1]([N:5]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CC(C(=O)O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N1CC(CO)C1

Procedure:
N-t-Butylazetidine-3-carboxylic acid (5.0 g., 0.318 mol.) was added portionwise to a slurry of 1.81 g. (0.0477 mol.) of lithium aluminum hydride in 135 ml. of tetrahydrofuran. The mixture was refluxed for 12 hours, cooled and 2 ml. of water and 2 ml. of 15% aqueous sodium hydroxide were added followed by an additional 6 ml. of water. The mixture was filtered and the precipitate was washed with ether. The filtrate and washings were combined and evaporated to dryness to give N-t-butyl-3-hydroxymethylazetidine, b.p. 124°-127° (27 mm.).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]>C(=O)([O-])[O-].[K+].[K+].[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1)#[N:2]
Reactant: N#Cc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(CCC(=O)O)cc1

Procedure:
100.1 g (0.578 mol) of 4-cyano-cinnamic acid are taken up in 1400 ml 1N potassium carbonate solution and hydrogenated over palladium-charcoal at 5 bar for 2.5 hours. Then the solution is made slightly acidic and the precipitate is suction filtered, and then dried in the circulating air drier.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>O1CCOCC1>[O:29]=[C:28]1[CH2:27][CH2:26][C:25](=[O:30])[N:1]1[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)C=Cc1ccc(N)nc1
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)CCC2=O)nc1
Yield: 66.4 %

Procedure:
A solution of 3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (1.40 g, 4.37 mol) and succinic anhydride (520 mg, 5.24 mmol) in 1,4-dioxane (50 mL) was heated to reflux for 5 h. Another portion of succinic anhydride (520 mg, 5.24 mmol) was then added, and the solution was maintained at reflux overnight. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2, and the solution was washed with satd NaHCO3, water and brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 97:3) gave the title compound (1.40 g, 76%) as an off-white solid and as a mixture of amide rotamers: mp 185-187° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92-8.88 (m, 1H), 8.41-8.32 (m, 1H 7.69-7.64 (m, 1H), 7.52-7.34 (m, 4H), 7.15-7.09 (m, 1H), 7.04-6.99 (m, 1H), 6.44-6.21 (m, 1H), 5.08-4.87 (m, 2H), 3.73-3.70 (m, 3H), 3.14-3.00 (m, 3H), 2.83-2.81 (m, 4H); MS (ESI) m/e 403 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c1C
Yield: 55 %

Procedure:
5-Fluoro-1,3-dihydroindol-2-one (0.54 g, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 0.83 g (55%) of the title compound as a yellow green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[NH:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][O:13][CH:6]([CH2:5][NH:4][C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[Cl:1])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1cccc(CBr)c1
Reactant: OC(CNc1ccc(Cl)cc1Cl)Cn1ccnc1
Product: Clc1cccc(COC(CNc2ccc(Cl)cc2Cl)Cn2ccnc2)c1

Procedure:
Reaction of 1-[3-(2,4-dichloroanilino)-2-hydroxypropyl]-imidazole with 3-chlorobenzyl bromide yields 1-[2-(3-chlorobenzyloxy)-3-(2,4-dichloroanilino)-propyl]-imidazole; M.P. of oxalate salt is 118°-119° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(#N)C>[N+:40]([C:39]1[C:34]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:35][CH:36]=[CH:37][CH:38]=1)([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 107.8 %

Procedure:
To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (320 mg, 1.0 mmol) in acetonitrile (˜5 mL), was added Hunig's base (190 μL, 1.1 mmol, 1.1 eq.) and 2-chloro-3-nitropyridine (175 mg, 1.1 mmol, 1.1 eq.) and the mixture stirred at reflux for 4 hours. The reaction mixture was then concentrated in vacuo and partitioned between saturated NaHCO3 solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (475 mg, 100%) as a yellow oil. LRMS APCI+ m/z 441 [MH]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])#[N:2]>[Pd].CO>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:12]([OH:14])=[O:13])#[N:2]
Reactant: N#CCCCCCCCCC(C(=O)OCc1ccccc1)C1CCCC1
Agent: [Pd]
Solvent: CO
Product: N#CCCCCCCCCC(C(=O)O)C1CCCC1
Reaction time: 2 h

Procedure:
A mixture of the cyanoester from step 3 (2.89 g, 8 mmol) and 10%, Pd-C (0.6 g, DeGussa, H2O content 50%) in anhyd MeOH (35 mL) was hydrogenated for 2 h (42-26 psi). The reaction mixture was filtered through a Celite® pad and concentrated to a colorless oil (2.02 g). 1H NMR (300 MHz, CDCl3) δ2.35(t, 8 Hz, 2H), 2.20 (m, 1H), 2.00(m, 1H), 1.3-1.9 (m, 22H).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCC(O)N1
Reactant: CCCCCCCCCO
Product: CCCCCCCCCOC1CCC(=O)N1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 5 g of 5-hydroxy-pyrrolidin-2-one 2.5 g of Amberlite IR 120H in 100 cm3 of n-nonanol is agitated at 60° C. for 3 hours. It is then cooled. the resin is filtered off, and the solvent is eliminated by distilling at 70° C. under 0.5 mbar. The residue is taken up in 50 cm3 of n-hexane, which is maintained for 16 hours at 5° C. After separating, 6.8 g of the expected product is obtained, m.p. 46°-48° C. After recrystallizing from n-hexane, m.p. 51°-52° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH:21]([C:24]1([OH:28])[CH2:27][NH:26][CH2:25]1)([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:26]3[CH2:27][C:24]([CH:21]([CH3:23])[CH3:22])([OH:28])[CH2:25]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)C1(O)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1(O)CN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (69 mg, 0.23 mmol) in DCE (5 mL) was added 3-isopropyl-azetidin-3-ol (27 mg, 0.23 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (99 mg, 0.47 mmol) was added and the resulting mixture stirred for a further 2 days. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) to give the title compound as a pale yellow oil (30 mg, 33%). LCMS (Method H): RT=2.65 min, [M+H]+ 395.5
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[Cl:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:43][C:42]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[CH:22][C:21]=1[NH:20][C:7]([C:5]1[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:8]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Reactant: Cc1nn(C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: Cc1nn(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Yield: 24.3 %

Procedure:
In the same manner as in Example 55 and using 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (58.2 mg, 0.415 mmol), tetrahydrofuran (5 mL), thionyl chloride (71.7 μL, 0.826 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (129 mg, 0.375 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (42.5 mg, 24%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (1.5 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-chiorophenyl isocyanate (641 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally crystallized with methanol-ether (1:6) to give 8f as solid. Yield: 1.06 g, 80.70%.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][N:27](COCC[Si](C)(C)C)[N:26]=4)=[CH:21][C:20]=3[CH3:38])=[C:12]2[N:11]=1)([CH3:3])[CH3:2].C([C@H]1COC(=O)N1C1C=CN2N=CC(C3C=CC(C4N(COCC[Si](C)(C)C)N=CN=4)=CC=3C)=C2N=1)(C)C>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][NH:27][N:26]=4)=[CH:21][C:20]=3[CH3:38])=[C:12]2[N:11]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2ncn(COCC[Si](C)(C)C)n2)ccc1-c1cnn2ccc(N3C(=O)OC[C@@H]3C(C)C)nc12
Agent: Cc1cc(-c2ncnn2COCC[Si](C)(C)C)ccc1-c1cnn2ccc(N3C(=O)OC[C@@H]3C(C)C)nc12
Product: Cc1cc(-c2nc[nH]n2)ccc1-c1cnn2ccc(N3C(=O)OC[C@@H]3C(C)C)nc12
Yield: 80 %

Procedure:
(4S)-4-isopropyl-3-(3-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.250 g, 80%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (4S)-4-isopropyl-3-(3-(2-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one and (4S)-4-isopropyl-3-(3-(2-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.414 g, 0.776 mmol), to produce a yellow solid. LCMS (APCI+) m/z 404.6 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 11.07 (broad s, 1H), 8.61 (d, J=7.8 Hz, 1H), 8.22 (m, 2H), 8.03 (d, J=7.8 Hz, 1H), 7.99 (s, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 4.84-4.80 (m, 1H), 4.38-4.30 (m, 2H), 2.72-2.64 (m, 1H), 2.51 (s, 3H), 0.94 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[C:20]3[CH:19]=[C:18]4[C:21]([CH3:29])([CH3:28])[C:22]5[C:27]([C:17]4=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:5]=[C:4](Br)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:31]1([C:2]2[CH:7]=[C:6]([N:8]3[C:20]4[CH:19]=[C:18]5[C:21]([CH3:29])([CH3:28])[C:22]6[C:27]([C:17]5=[CH:16][C:15]=4[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(Br)nc(Br)c4)c3cc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(-c5ccccc5)nc(-c5ccccc5)c4)c3cc21

Procedure:
25 g (48 mmol) of 10-(2,6-dibromopyridin-4-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene and 12.9 g of phenylboronic acid (106 mmol) are suspended in 300 ml of ethylene glycol dimethyl ether. 75 ml of a 2 M Na2CO3 solution are added to the reaction mixture. 2.8 g (2.4 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 12 h. After cooling, the precipitated solid is filtered off with suction and washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 15 g, 60% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O.[OH-].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:16]=[C:15]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:14]=1
Reactant: NC1CCCCCC1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Yield: 70.5 %

Procedure:
To a sample of compound 101 (20.02 g, 65.6 mmol) in acetone (200 mL) was added cycloheptylamine (8.3 mL, 65.5 mmol) in acetone (55 mL) slowly by addition funnel at rt. Then water (66 mL) was added followed by aqueous sodium hydroxide (26.2 mL, 2.5 N, 65.5 mmol) by addition funnel. The reaction mixture was heated at reflux under a nitrogen atmosphere for approximately about 3 hours. The reaction was cooled, diluted with ethyl acetate, washed 1 time with water, and finally 1 time with brine. The organic layer was separated and dried over potassium carbonate/sodium sulfate. The organic layer was filtered and concentrated in vacuo. The product (24.13 g) was purified by flash column chromatography (silica gel, 1:4 ethyl acetate:hexanes). The fractions were combined and concentrated in vacuo to afford 133 as a pale yellow solid (17.66 g, 70.5%), mp 146° C.; HPLC: Inertsil ODS-3V C18, 40:10:50 [KH2PO4 (0.01M, pH 3.2): CH3OH:CH3CN], 264 nm, Rt 58.8 min, 99.9% purity); MS (ESI): m/z 382 (M+H, 100), 241 (2.8), 226 (8.4), 139 (43.5), 116 (6).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.C([OH:23])C.CN(C)C=O>[OH-].[Na+]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:4]2[NH:3][C:2](=[O:23])[C:11]3[C:6](=[N:7][CH:8]=[CH:9][N:10]=3)[N:5]=2)=[CH:15][CH:16]=1
Reactant: CCO
Reactant: Nc1nc(COc2ccc(Cl)cc2)nc2nccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(COc2ccc(Cl)cc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 17.5 g (0.0608 mole) of crude 4-amino-2-[(4-chlorophenoxy)methyl]pteridine in 1750 ml of 5% aqueous sodium hydroxide. Heating time: 1 hours 30 minutes under reflux. Yld: 8.7 g (50%), m.p. 267°-269° C. (ethanol/N,N-dimethylformamide).