Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Br:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc([N+](=O)[O-])c1Br
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2Br)c2c[nH]nc2N1

Procedure:
A suspension of 2-bromo-3-nitrotoluene (5.1 g), N-bromosuccinimide (4.2 g) and benzoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g). The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid-water (1:1, 16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-bromo-3-nitrobenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-bromo-3-nitrobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][CH3:34])[CH2:19][CH2:18]1.C(N(CC)CC)C.[C:43](Cl)(Cl)=[S:44]>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:33]([CH3:34])[C:43]2=[S:44])[CH2:19][CH2:18]1
Reactant: CNc1ccccc1C(=O)NCCN1CCC(Cc2nc3cccnc3n2Cc2ccco2)CC1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=S)n(CCN2CCC(Cc3nc4cccnc4n3Cc3ccco3)CC2)c(=O)c2ccccc21
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a stirred mixture of 8 parts of N-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2-(methylamino)benzamide, 13 parts of N,N-diethylethanamine and 130 parts of dichloromethane was added dropwise a solution of 2.3 parts of carbonothioic dichloride in dichloromethane. Upon completion, stirring was continued for 2 hours. The reaction mixture was evaporated. The residue was crystallized from a mixture of methanol and ethanol. The product was filtered off and boiled in methanol. The product was filtered off and dried, yielding 3 parts (34.3%) of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-1-methyl-2-thioxo-4(1H)-quinazolinone; mp. 169.2° C. (486).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH2:21][OH:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1.CCOC(C)=O>[CH3:26][S:27]([O:22][CH2:21][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[C:12](=[C:11]([C:23](=[O:24])[NH2:25])[CH:10]=[CH:9][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:13][C:14]=2[CH:15]=1)(=[O:29])=[O:28]
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(CO)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-fluorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-1, 223 mg, 0.667 mmol) and TEA (0.279 mL, 2.001 mmol) in THF (8 mL) was treated with methanesulfonyl chloride (0.104 mL, 1.334 mmol). The resulting suspension was stirred at rt for 15 min. The mixture was diluted with EtOAc, washed with water and brine, and dried and concentrated to provide crude (8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl)methyl methanesulfonate as a yellow glassy foam (300 mg, ca. 50% purity). A portion of this material (80 mg, 0.097 mmol) was dissolved in DMF (1 mL), treated with morpholine (84 mg, 0.970 mmol) and heated at 45° C. for 3 days. The mixture was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-(morpholinomethyl)-9H-carbazole-1-carboxamide (9.6 mg, 23%). 1H NMR (400 MHz, methanol-d4) δ 7.94 (1 H, d, J=7.8 Hz), 7.59 (1 H, s), 7.52-7.58 (1 H, m), 7.48-7.52 (1 H, m), 7.33-7.39 (1 H, m), 7.30 (1 H, t, J=9.0 Hz), 7.21 (1 H, d, J=8.3 Hz), 7.14 (1 H, d, J=7.8 Hz), 6.99 (1 H, dd, J=8.3, 1.5 Hz), 3.81 (2H, s), 3.71-3.77 (4 H, m), 2.66 (4 H, br. s.). Mass spectrum m/z 404.2 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>CCCCCC.C1COCC1>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
21.2 ml (52.7 mmol) of a 2.5 M solution of n-butyllithium in n-hexane were added dropwise to a solution, cooled to −78° C., of 7.4 ml (52.7 mmol) of diisopropylamine in 20 ml of abs. THF. During the addition, the reaction temperature was kept below −60° C. After 30 min of stirring at −60° C. to −70° C., this solution was added dropwise to a solution, cooled to −78° C., of 5.0 g (35.2 mmol) of tert-butyl cyclopropanecarboxylate and 15.2 g (70.3 mmol) of 1,4-dibromobutane in 20 ml of abs. THF. After the end of the addition, cooling was removed and the mixture was slowly warmed to RT with stirring. After a further 5 h of stirring at RT, the reaction mixture was added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 50:1). This gave 4.62 g (44.6% of theory) of the target compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][S:6][C:7]1[C:11]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][S:9][N:8]=1)[CH3:2].S(=O)(=O)(O)[OH:20].B1([O-])OO1.O.O.O.O.[Na+]>CO>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:7]1[C:11]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][S:9][N:8]=1)=[O:20])[CH3:18]
Reactant: CCN(CC)CCSc1nsnc1-n1ccnc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CO
Solvent: O
Product: CCN(CC)CCS(=O)c1nsnc1-n1ccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of the compound of Example 10 in methanol istreated slowly with excess 30% sulfuric acid an then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide and filtered. The filter cake is washed with methylene chloride and the aqueous filtrate extracted with the methylene chloride washings. The combined extract is washed with water, dried, and concentrated to obtain the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:45]([Cl:47])[Cl:46]>C(O)(=O)C>[NH3:1].[CH2:45]([Cl:47])[Cl:46].[CH2:19]([N:21]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH3:20]
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: CCNCc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(Cc1ccncc1)Cc1ccc(OCCCN2CCCCC2)cc1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (222 mg) ethyl-pyridin-4-ylmethyl-amine (122 mg), and acetic acid (0.06 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (246 mg). 1H NMR (400 MHz, CDCl3): 8.51 (m, 2H), 7.29 (m, 2H), 7.24 (m, 2H), 6.84 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.52 (s, 2H), 3.50 (s, 2H), 2.51-2.44 (m, 4H), 2.40 (br, 4H), 1.97 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H), 1.06 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH2:15][CH2:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=1.[C:16]([N:24]=C=O)(=[O:23])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>C(Cl)Cl.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH2:15][CH2:14][N:13]([C:16]([NH2:24])=[O:23])[C:10]3=[N:11][CH:12]=2)[CH:2]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: c1cncc(-c2cnc3c(c2)CCN3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)N1CCc2cc(-c3cccnc3)cnc21
Temperature: 50 °C
Yield: 63.3 %

Procedure:
5-Pyridin-3-yl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.25 mmol) and benzoyl isocyanate (62 mg, 0.38 mmol) are dissolved in 1.5 mL of DCM. The mixture is heated at 50° C. for 16 hrs. Then the solvent is removed in vacuum and the residue is dissolved in 1.5 mL of EtOH. K2CO3 (60 mg, 0.43 mmol) is added and the mixture is heated at 80° C. for 55 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added DMSO:EtOAc (1:3 mL) mixture and the white solid formed is filtered, rinsed with more EtOAc and dried to give 38 mg of the titled product.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:11][CH:10](C(O)=O)[C:9]1=[O:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([C@@H:12]2[NH:8][C:9](=[O:26])[CH2:10][CH2:11]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C(=O)O)C[C@@H]1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of (5R)-1-(tert-butoxycarbonyl)-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidine-3-carboxylic acid obtained in Step E (ca. 1.21 mmol) and 30% TFA in DCM (6 mL) is stirred at rt for 30 min. The reaction mixture is then dissolved in DCM (120 mL), washed with saturated aq. NaHCO3 (40 mL) and brine (40 mL) and dried over Na2SO4. Concentration to give (R)-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one as a slight brown solid (278 mg, 100% overall yield for two steps). This product is used for the next step without further purification. HPLC-MS calculated for C11H10F3NO (M+H+) 230.07, found 230.00.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=[O:21])[CH2:14]2>>[OH:21][C:15]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Product: OC1(c2ccncc2)CN2CCC1CC2
Yield: 56.8 %

Procedure:
By the procedure described in Description 1, n-butyl lithium (1.6M in hexanes, 19.5 ml, 31.2 mmol), 4-bromopyridine (5.37 g, 34.0 mmol) and 3-quinuclidinone (3.90 g, 31.2 mmol) gave 3.62 g of the title compound as a tan powder. The dihydrochloride salt was prepared; m.p. 225°-235° C.; Found: C, 50.50; H, 6.39; N, 9.76. C12G20N2, Cl2O.0.5H2O requires C, 50.36; H, 6.69; N, 9.79; δ(360 MHz, D2O) 8.854 (2H, d, J=6.8 Hz, py-H), 8.207 (2H, d, J=6.8 Hz, py-H), 4.016 (1H, d, J=14.2 Hz, H-2ax), 3.696 (1H, d, J=14.2 Hz, H-2eq), 3.52-3.30 (4H, m, H2 -6 and H2 -7), 2.70-1.60 (5H, m, H-4, H2 -5 and H2 -8); m/e 204 (M+).
Reaction SMILES: C[Al](C)C.[CH:5]1([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23]C)=O)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH2:42])[NH:40][N:41]=2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1(C)C=CC=CC=1>[CH:5]1([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[N:16]=[CH:17][C:18]([C:21]([NH:42][C:39]4[NH:40][N:41]=[C:37]([CH2:36][CH2:35][C:29]5[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:27]([O:26][CH3:25])[CH:28]=5)[CH:38]=4)=[O:23])=[CH:19][N:20]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cnc(N2CCCN(C3CC3)CC2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C5CC5)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 1.5 %

Procedure:
Trimethylaluminium (1.402 ml, 2.80 mmol) was added dropwise to a stirred suspension of methyl 2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (310 mg, 1.12 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (277 mg, 1.12 mmol) in toluene (5.61 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (8.00 mg, 1%) as a cream solid. Some impure fractions were combined and concentrated to dryness and purified by crystallisation from MeCN to afford the title compound (51 mg, 9%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[N:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1N1CCOC1=O
Product: COc1ccc(CC(=O)Nc2ccsc2N2CCOC2=O)cc1

Procedure:
The title compound was prepared from 3-(3-aminothiophen-2-yl)oxazolidin-2-one and 2-(4-methoxyphenyl)acetic acid (510 mg, 3.06 mmol) using protocol B. The crude product was purified by HPLC. Method [7] Retention time 2.95 min by HPLC (MH+ 333). 1H NMR (300 MHz, CDCl3) δ 8.14 (broad s, 1H), 7.39 (d, J=5.7 Hz, 1H), 7.27 (d, J=9.0 Hz, 2H), 7.06 (d, J=5.7 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 4.47 (m, 2H), 3.89 (m, 2H), 3.83 (s, 3H), 3.64 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[O:17][CH2:18][C:19]2([N:41]=1)[C:28]1([CH2:31][O:30][CH2:29]1)[CH2:27][O:26][C:25]1[C:20]2=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:24]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:43]1[CH:44]=[N:45][CH:46]=[C:47]([C:49]#[C:50][CH2:51][O:52][CH3:53])[CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O>[CH3:53][O:52][CH2:51][C:50]#[C:49][C:47]1[CH:48]=[C:43]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[O:26][CH2:27][C:28]2([CH2:31][O:30][CH2:29]2)[C:19]23[CH2:18][O:17][C:16]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[N:41]2)[CH:44]=[N:45][CH:46]=1
Reactant: COCC#Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OCC21COC1
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: O
Solvent: C1COCCO1
Product: COCC#Cc1cncc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, a mixture of di-tert-butyl[6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (213 mg, 0.372 mmol), 3-bromo-5-(3-methoxyprop-1-yn-1-yl)pyridine (252 mg, 1.12 mmol), Na2CO3 (158 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (21.5 mg, 0.019 mmol), dioxane (3.4 mL) and water (0.85 mL) was stirred for 3 hours at 110° C. The reaction mixture was cooled down to ambient temperature, and water was added to the mixture. The mixture was extracted with MeOH—CHCl3 (1:9), and the organic layer was dried over Na2SO4 prior to filtration. The filtrate was concentrated at reduced pressure to give crude di-tert-butyl {6′-[5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl}imidodicarbonate, which was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38].C(NC(C)C)(C)C>[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:38]#[C:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1
Reactant: C#Cc1ccccn1
Reactant: CC(C)Oc1cc(OCCCN2CCOCC2)cc2ncnc(Nc3c(Cl)cc(I)c4c3OCO4)c12
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(OCCCN2CCOCC2)cc2ncnc(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)c12
Temperature: -10 °C

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-5-isopropoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.162 g), 2-ethynyl pyridine (0.03 ml), palladium(II) bis-triphenylphosphine dichloride (0.020 g) and copper (I) iodide (0.006 g) was taken up into ethyl acetate (5 ml) and cooled to −10° C. This was set to stir rapidly, then diisopropylamine (0.047 ml) was added and the reaction was stirred cold for 30 minutes before being warmed to room temperature and left to stir for 18 hours. The reaction mixture was then filtered through Celite under suction (washing the Celite with a further portion of ethyl acetate) then the combined filtrate solutions were evaporated under reduced pressure to give a brown gum. This was then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained the title compound (0.090 g) as a pale brown foam; NMR Spectrum: (CDCl3) 1.54 (d, 6H), 2.04 (quin, 2H), 2.50 (m, 4H), 2.56 (t, 2H), 3.74 (t, 4H), 4.16 (t, 2H), 4.83 (sept, 1H), 6.14 (s, 2H), 6.50 (d, 1H), 6.84 (d, 1H), 7.19 (s, 1H), 7.25 (m, 1H), 7.54 (d, 1H), 7.68 (td, 1H), 8.53 (s, 1H), 8.63 (dd, 1H), 9.46 (s, 1H); Mass Spectrum: M+H+ 602/604.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])(CC)C.I[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[C:34]([O:35][CH2:36][O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=[C:31]([O:41][CH2:42][O:43][CH3:44])[C:30]=1[O:45][CH3:46].C(OCC)C>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:8]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[C:34]([O:35][CH2:36][O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=[C:31]([O:41][CH2:42][O:43][CH3:44])[C:30]=1[O:45][CH3:46]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCI)c1OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
280 Milligrams (1.08 mmoles) of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in a mixed solvent of 5 ml of tetrahydrofuran with 1 ml of hexamethylphosphoric triamide, then this solution was cooled to -78° C. in a dry ice-acetone bath. To this cooled solution was added 1.08 ml (1.21 mmoles) of secbutyllithium (1.21 M, cyclohexane solution) and the mixture was stirred for 30 minutes, then 2 ml of tetrahydrofuran solution containing 440 mg (1.0 mmole) of 1-(4-iodobutyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was added thereto and stirred for 12 hours. The reaction mixture was concentrated, to the residue obtained was added 60 ml of diethyl ether, and washed twice with water, then washed twice with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The dried diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a silica gel column chromatography (diameter 2 cm×length 20 cm, eluent: 20% ethyl acetate-benzene) to obtain 467 mg of 2,2'-tetramethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene]. Colorless oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ccc(B(O)O)cn1
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: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cn1
Temperature: 120 °C
Yield: 60.9 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (660 mg, 1.80 mmol) was dissolved in 18 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 6-Methoxypyridin-3-ylboronic acid (358 mg, 2.34 mmol), 2.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 102 mg, 0.0882 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness and then purified on 40 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (482 mg, 61%). ESI-MS m/z calc. 439.1. found 440.1 (M+1)+ Retention time 1.95 minutes.