Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[F:18][C:19]([F:30])([F:29])[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21]>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([NH:22][C:20](=[O:21])[C:19]([F:18])([F:29])[F:30])[CH2:24]2)[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(NC1CCCNC1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1cc(N2CCCC(NC(=O)C(F)(F)F)C2)ncn1
Temperature: 170 °C
Reaction time: 24 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.149 g, 1.15 mmol) and diisopropylethylamine (0.446 g, 3.45 mmol) were suspended in n-butanol. 2,2,2-Trifluoro-N-piperidin-3-ylacetamide 9-3 (0.226 g, 1.15 mmol) was then added. The reaction was stirred at 170° C. for 24 hours. The butanol was then removed under reduced pressure and the product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5). 1H-NMR (CD3OD): 8.06 ppm (s, 1H); 5.82 ppm (s, 1H); 4.27 ppm (d, 1H); 4.15 ppm (d, 1H); 3.85 ppm (m, 1H); 3.73 ppm (p, 3H); 3.23 ppm (q, 3H); 3.08 ppm (dd, 2H); 2.13 ppm (m, 1H); 1.85 ppm (m, 1H); 1.71 ppm (m, 1H); 1.62 ppm (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:17]([CH3:20])=[CH:16][N:15]=[CH:14][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:69][O:70][C:71]1[CH:72]=[C:73]([CH:75]=[CH:76][C:77]=1[O:78][CH3:79])[NH2:74]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:69][O:70][C:71]1[CH:72]=[C:73]([NH:74][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[S:19][C:18]5[C:17]([CH3:20])=[CH:16][N:15]=[CH:14][C:13]=5[CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:75]=[CH:76][C:77]=1[O:78][CH3:79]
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1cncc2cc(-c3cnc4ccc(Cl)nn34)sc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4cc5cncc(C)c5s4)n3n2)cc1OC
Temperature: 110 °C

Procedure:
To a solution of 6-chloro-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (31 mg, 0.103 mmol, 1.0 equiv), xantphos (12 mg, 0.0206 mmol, 0.2 equiv), palladium acetate (2 mg, 0.0103 mmol, 0.1 equiv), and potassium carbonate (284 mg, 2.06 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (24 mg, 0.155 mmol, 1.5 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 20 mg, of the brown solid, 47%.
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.[C:10]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:17]([O:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:17]([O:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:2][CH3:1])=[O:26])=[CH:23][CH:22]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ccc(C(=O)OCc2ccc(C(=O)Cl)cc2)cc1C(C)(C)C
Reactant: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 ml of methanol, 460 μl of triethylamine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 1.2 g (3.3 mmol) of 4-(3-tert-butyl-4-methoxybenzoyloxymethyl)benzoyl chloride dissolved in 30 ml of THF is added dropwise and the mixture is stirred at room temperature for 4 h.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C(O)C>[O:30]=[S:29]1(=[O:31])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:4]([C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]3[CH:18]=[CH:19][CH:20]=[C:8]3[C:7]=2[OH:21])=[N:32]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Solvent: CCO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccn21
Temperature: 180 °C
Yield: 50 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.040 g, 0.14 mmol) was mixed with 2-amino-benzenesulfonamide (0.0235 g, 0.14 mmol) and the resulting mixture was heated to 180° C. for 20 min. The resulting crude oil was allowed to cool to 25° C. and ethanol (0.5 mL) was added and sonicated to afford a tan precipitate, which was collected and dried in vacuo. The crude solid was dissolved in 1.0 M aqueous potassium hydroxide solution (0.3 mL) and heated to 110° C. for 20 h. The reaction mixture was allowed to cool to 25° C. and 10% aqueous hydrochloric acid solution (0.5 mL) was added and the resulting white precipitate was collected. The solid was washed with methanol and dried in vacuo to afford the desired product, 3-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-4-hydroxy-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.028 g, 0.07 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.97 (6H, d, J=6.4 Hz), 1.28 (2H, bs), 1.61 (2H, q, J1=15.2 Hz, J2=6.8 Hz), 1.74 (1H, m), 4.43 (2H, t, J=8.0 Hz), 6.71 (1H, dd, J1=4.4 Hz, J2=2.4 Hz), 7.04 (1H, d, J=4.4 Hz), 7.23 (1H, t, J=8.0 Hz), 7.50 (1H, t, J=7.6 Hz), 7.63 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=8.0 Hz), 7.90 (1H, m); LC-MS (ESI) calcd for C19H20N4O4S 400.45, found 401.28 [M+H+].
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCCCCCCCCCOCc1ccccc1
Yield: 65.7 %

Procedure:
First, 2.4 g of 60% sodium hydride and 100 ml of dry tetrahydrofuran were placed in a 300 ml flask whose content was replaced with argon. Then, 15 ml of a tetrahydrofuran solution containing 11.3 g of benzyl bromide, 15 ml of a tetrahydrofuran solution containing 15.9 g of 12-bromododecanol, and 0.1 g of tetrabutylammonium iodide were added to the reaction mixture. The resultant reaction mixture was stirred under reflux for 2.5 hours. The reaction mixture was poured into water, and an organic layer was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/3) to obtain 14.0 g of 1-bromo-12-benzyloxydodecane (Y: 65.7%). The compound thus obtained had a purity of 98.4% by GC.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:21])[CH:14]=[C:13]([C@@H:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][N:29]3C(OC(C)(C)C)=O)[CH3:23])[N:12]=1.O>C1COCC1>[N:33]1[C:25]([NH:24][C@H:22]([C:13]2[N:12]=[C:11]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:21])[CH3:23])=[C:26]2[C:30]([NH:29][CH:28]=[N:27]2)=[N:31][CH:32]=1
Reactant: CC(=O)NCCO
Reactant: C[C@H](Nc1ncnc2c1ncn2C(=O)OC(C)(C)C)c1cc2cccc(Cl)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCOc1nc([C@H](C)Nc2ncnc3[nH]cnc23)cc2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of N-(2-hydroxyethyl)acetamide (110 mg, 1.07 mmol, 2.43 eq) in THF (20 mL) at 0° C., NaH (60% in mineral oil, 110 mg, 2.75 mmol, 6.25 eq) was added and the resulting mixture was stirred for 15 min. To this mixture, (S)-tert-butyl 6-(1-(1,8-dichloroisoquinolin-3-yl)ethylamino)-9H-purine-9-carboxylate 39 (200 mg, 0.44 mmol, 1.0 eq) was added. The resulting mixture was stirred at reflux for 2 h, cooled to RT and then poured into water (30 mL). The mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)—N-(2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)ethyl)acetamide 40. ESI-MS m/z: 426.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=3[C:25]3[CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][C:34]=4[CH3:43])[CH:28]=[CH:29][C:30]=3[O:31][CH3:32])[C@H:9]2[CH3:44])[CH:5]=[CH:4][N:3]=1.[CH3:45]B1OB(C)OB(C)O1>C1COCC1.C([O-])([O-])=O.[K+].[K+].O.CCOC(C)=O>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][C:34]=2[CH3:43])=[CH:26][C:25]=1[C:16]1[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=1[CH2:14][N:10]1[C@@H:9]([CH3:44])[C@@H:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:45])[CH:7]=2)[O:12][C:11]1=[O:13]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(Cl)c4)[C@@H]3C)c2)c(C)c1
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(C)c4)[C@@H]3C)c2)c(C)c1
Temperature: 80 °C

Procedure:
To a solution of methyl 2″-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (48 mg, 0.077 mmol) in THF (1 mL) and K2CO3 (1N) (1 mL) was added trimethylboroxine (0.107 mL, 0.768 mmol) and 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (7.1 mg, 0.011 mmol) The mixture was sealed and heated at 80° C. overnight. The mixture was diluted with water and EtOAc and filtered through Celite. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=605.2; found=605.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.49 (t, J=4.3 Hz, 1 H); 7.98 (t, J=6.6 Hz, 1 H); 7.91 (t, J=10.0 Hz, 1 H); 7.73 (s, 0.5 H); 7.67 (s, 0.5 H); 7.65 (s, 1 H); 7.47-7.39 (m, 2 H); 7.33-7.26 (m, 1 H); 7.15 (dd, J=2.2, 5.7 Hz, 1 H); 7.09 (dd, J=6.8, 8.4 Hz, 1 H); 7.06 (s, 0.5 H); 7.00 (s, 0.5 H); 6.95 (d, J=4.8 Hz, 0.5 H); 6.90 (d, J=4.7 Hz, 0.5 H); 5.43 (d, J=8.2 Hz, 0.5 H); 5.18 (d, J=8.1 Hz, 0.5 H); 4.92 (d, J=15.8 Hz, 0.5 H); 4.87 (d, J=15.8 Hz, 0.5 H); 4.22 (d, J=15.8 Hz, 0.5 H); 4.00 (d, J=15.8 Hz, 0.5 H); 3.95 (s, 3 H); 3.89 (s, 1.5 H); 3.88 (s, 1.5 H); 3.81-3.73 (m, 1 H); 2.57 (s, 1.5 H); 2.56 (s, 1.5 H); 2.39 (s, 1.5 H); 2.34 (s, 1.5 H); 0.57 (d, J=6.6 Hz, 1.5 H); 0.47 (d, J=6.6 Hz, 1.5 H).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:27]([N:34]1[CH2:38][C@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)[C@@H:36]([CH:47]=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:35][C@H:36]([CH:47]=[CH2:2])[C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)[CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a suspension of methyltriphenylphosphonium iodide (6.35 g, 15.6 mmol) in THF (60 mL) was added n-BuLi (1.6N in heptane, 7.4 mL, 0.0119 mol) dropwise at 0° C. and stirred for one hour. To this reaction mixture was added a solution of (3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carbaldehyde 2.77 g (9.2 mmol) in THF (15 mL) dropwise at 0° C. and stirred for another one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate. The separated organic layer was dired on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (7:3) yielding 1.7 g (62%) of the title compound as a light yellow oil ES-MS m/e: 300.1 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[CH:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].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:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Ic1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame-dried flask under nitrogen, 0.53 mL (3.79 mmol) of diisopropylamine were dissolved in 5 mL of tetrahydrofuran (THF) and the solution cooled to −78° C. n-Butyllithium (3.75 mmol as a 2.5 M solution in hexanes) was added and the resulting mixture brought to 0. ° C. with continued stirring for 10 min. The reaction mixture was again cooled to −78° C. and to this mixture added a solution of 1.0 g (3.40 mmol) of the product from Method C in 10 mL of THF over a 10 min period. The reaction mixture was stirred for 1 h at −78° C., at which time, 8.2 mL (4.10 mmol) of a 0.5 M solution of zinc chloride in THF was added, the reaction mixture was brought to room temperature and stirred for 1 h. Iodobenzene (0.46 mL/4.11 mmol) and a suspension of 197 mg of tetrakis(triphenylphosphine)palladium in 2 mL of THF were added. The resulting mixture was stirred at reflux for 3 h., cooled to room temperature, and partitioned between dichloromethane and water. The aqueous layer was acidified with 1 N HCl and extracted twice with dichloromethane. The dichloromethane layers were combined, washed with 1 N HCl and brine, dried over magnesium sulfate (MgSO4), filtered and concentrated in vacuo to obtain the title compound. LRMS: 370, 372 (M+2).
Reaction SMILES: Cl.[O:2]([CH2:9][C:10](=[NH:12])[NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH:16]([CH3:33])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=O.O>ClCCl.CN(C)C=O.C(OCC)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([C:17]3[N:12]=[C:10]([CH2:9][O:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[NH:11][C:16]=3[CH3:33])=[CH:20][CH:21]=2)=[CH:27][CH:28]=1
Reactant: CC(Br)C(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: N=C(N)COc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1[nH]c(COc2ccccc2)nc1-c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 50 °C

Procedure:
620 mg of 2-phenoxyethanimidamide hydrochloride (0.00333 mol) are desalified in dichloromethane by the action of a 3N sodium hydroxide solution. After decantation and extraction of the aqueous phase by dichloromethane, the organic phase is dried over sodium sulphate then evaporated to dryness. The white powder obtained is solubilized in dimethylformamide (30 ml). 275 mg of 2-bromo-1-[4-(4-fluorophenoxy)phenyl]propan-1-one (0.000851 mol) is added. The mixture is heated at 50° C. for 20 hours then returned to 23° C. before adding 25 ml of water and 30 ml of ethyl acetate. After extraction with ethyl acetate, the organic phase is dried over sodium sulphate then evaporated in a rotary evaporator under vacuum. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 2-8). A pale yellow-coloured foam is obtained.
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11]1.C1(N2CCC(OC3C=CC(I)=CC=3)CC2)CCC1.[C:40]([N:44]1[CH2:49][CH2:48][CH:47]([O:50][C:51]2[CH:56]=[CH:55][C:54](I)=[CH:53][CH:52]=2)[CH2:46][CH2:45]1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]1[CH2:45][CH2:46][CH:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([N:10]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:11]3)=[CH:53][CH:52]=2)[CH2:48][CH2:49]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)N1CCC(Oc2ccc(I)cc2)CC1
Reactant: O=C(c1cc[nH]c1)N1CCCC1
Agent: Cn1ccc(C(=O)O)c1
Agent: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: CC(C)(C)N1CCC(Oc2ccc(-n3ccc(C(=O)N4CCCC4)c3)cc2)CC1

Procedure:
The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by (1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 1-tert-butyl-4-(4-iodophenoxy)piperidine (which can be synthesized in accordance with the method described in WO2008072724).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH3:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:22][CH3:23])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Product: COc1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1[C@@]21COCC(N)=N1
Temperature: 100 °C
Yield: 95.8 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.065 g, 0.173 mmol), 2-fluoropyridin-3-ylboronic acid (0.049 g, 0.346 mmol), potassium phosphate (0.110 g, 0.518 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.12 mg, 8.64 μmol). The vial was flushed with Ar (g), dioxane (0.648 mL) and water (0.216 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/EtOAc) to afford 65 mg of (S)-7-(2-fluoropyridin-3-yl)-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light yellow solid.
Reaction SMILES: [C:1]([O-:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C:17]2[N:28]=[C:27]3[C:20]([N:21]=[C:22]([NH:24][C:25]3=[O:26])[NH2:23])=[N:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6].[Na+].Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:47][O:48][C:49](=[O:60])[C@H:50]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][CH:54]=1)[NH2:51]>O>[CH3:47][O:48][C:49](=[O:60])[C@H:50]([CH2:52][C:53]1[CH:54]=[CH:55][C:56]([OH:59])=[CH:57][CH:58]=1)[NH2:51].[C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][C:17]2[N:28]=[C:27]3[C:20]([N:21]=[C:22]([NH:24][C:25]3=[O:26])[NH2:23])=[N:19][CH:18]=2)=[CH:29][CH:30]=1)=[O:10])[C:5]([OH:7])=[O:6]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc3)nc2c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: O
Product: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium folate (100 mg.) is dissolved in water (10 ml.). To this is added 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (100 mg.), followed by the addition of tyrosine methyl ester hydrochloride (32 mg.) dissolved in water (2 ml.). A yellow gelatinous precipitate forms. The mixture is stirred for four hours at room temperature. The precipitated material is extracted into ethyl acetate and washed successively with 1 N sodium bicarbonate (3×10 ml.) 1 N hydrochloric acid (3×10 ml.) and water (2×10 ml.). The solution is dried over anhydrous magnesium sulfate and the ethyl acetate removed on a rotary evaporator. Trituration of the remaining residues with hexane yields yellow crystalline folic acid tyrosine methyl ester conjugate weighing 56 mg.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>[Ni].CO.CN(C=O)C>[C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(N)cc12
Yield: 98.1 %

Procedure:
N1-phenyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (100 mg) (from step 1) was reduced using raney nickel (100 mg) in methanol (40 ml) and DMF (10 ml) in the presence of hydrazine hydrate (0.5 ml) under gentle reflux for 1 h. The reaction mixture was fliterd through celite and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (90 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[N:6]=[C:5]3[C:12]4[CH:13]=[CH:14][N:15]=[CH:16][C:17]=4[C:18](=[O:19])[C:3]=1[C:4]=23.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[N:6]=[C:5]3[C:12]4[CH:13]=[CH:14][N:15]=[CH:16][C:17]=4[C:18](=[O:19])[C:3]=1[C:4]=23
Reactant: CN(C)CCN
Reactant: Cn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Product: CN(C)CCNc1ccc2c3c(nn2C)-c2ccncc2C(=O)c13

Procedure:
5-chloro-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one of Example 6 (0.013 g) is added to 2-(dimethylamino)ethylamine (0.34 mL). The yellow mixture is heated quickly to reflux for 1 hour. The excess diamine is removed from the orange solution by a gentle stream of nitrogen. The orange mixture obtained is purified by silica gel column chromatography with a gradient elution (1% methanol/chloroform (25 mL), 2% methanol/chloroform (25 mL), 4% methanol/chloroform (25 mL), 8% methanol/chloroform (25 mL), 12% methanol/chloroform (25 mL), 16% methanol/chloroform (25 mL), 24% methanol/chloroform (50 mL)) to yield 5-[[2-(dimethylamino)ethyl]amino]-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one (0.010 g) as a reddish orange solid.