Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([I:9])[C:7]=1[OH:8].[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:12][C:11](=[O:13])[CH:10]([C:4]1[CH:3]=[C:2]([I:1])[C:7]([O:8][CH2:10][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)=[C:6]([I:9])[CH:5]=1)[CH3:14]
Reactant: BrCc1cccc(I)c1
Reactant: CC(C(=O)O)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C(=O)OCc1cccc(I)c1)c1cc(I)c(OCc2cccc(I)c2)c(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 183.5 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxyphenypropionic acid (209 mg, 0.5 mmol), 3-iodobenzyl bromide (371 mg, 1.25 mmol), and cesium carbonate (490 mg, 1.5 mmol) in 5 mL DMF was stirred for 15 h at room temperature. After that time, 1 M HCl (15 mL) was added and an oil formed. The oil was extracted with ether and methanol was added. Crystals formed in the solution upon cooling, yielding the title compound as white crystals (390 mg, 92%); 1H NMR (CDCl3) δ 8.00 (S, 1H), 7.71-7.60 (m, 6H), 7.29-7.26 (m, 1H), 7.16 (appar. t, J=7.8 Hz, 1H), 7.11 (appar. t, J=7.8 Hz, 1H), 5.05 (s, 2H), 4.91 (s, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:14])[CH:3]=1.O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Br)cc1C
Reaction time: 120 h

Procedure:
14.3 g of 4-bromo-2-methyl-5-nitrobenzoic acid were dissolved in 250 ml of MeOH and 11.6 g of SOCl2 were slowly added dropwise. The mixture was allowed to stand at RT for 5 days, the volatile components were removed in vacuo and the residue is recrystallized from DIP.
Reaction SMILES: C(Cl)(=O)C.Cl.C(OC([N:13]1[CH2:18][C@@H:17]([CH3:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:66])[NH:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[N:41]=[C:42]([C@@H:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[NH:43][CH:44]=5)=[CH:36][CH:35]=4)=[C:30]([O:61][C:62]([F:65])([F:64])[F:63])[CH:29]=3)=[CH:22][N:21]=2)[CH2:15][C@@H:14]1[CH3:67])=O)(C)(C)C>C(O)C>[CH3:59][O:58][C:56](=[O:57])[NH:55][C@H:51]([C:50]([N:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:42]1[NH:43][CH:44]=[C:40]([C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:32]=[CH:33][C:28]([NH:27][C:26]([C:23]4[CH:22]=[N:21][C:20]([N:16]5[CH2:15][C@H:14]([CH3:67])[NH:13][CH2:18][C@H:17]5[CH3:19])=[CH:25][CH:24]=4)=[O:66])=[CH:29][C:30]=3[O:61][C:62]([F:65])([F:63])[F:64])=[CH:35][CH:36]=2)[N:41]=1)=[O:60])[CH:52]([CH3:53])[CH3:54]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CCO
Solvent: CC(=O)Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)NC[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (63.2 mL, 888 mmol) was added to ethanol (360 mL) and stirred at RT for 1 h. To the resulting HCl solution was added a solution of (2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (73 g, 84 mmol) in ethanol (360 mL). The reaction mixture was stirred at RT overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[CH:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1)[CH:20]([CH3:25])[C:21]([F:24])([F:23])[F:22].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[CH:19]([N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1)[CH:20]([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: CC1CCN(C(C(=O)Nc2cc(CCC(=O)OC(C)(C)C)ccc2Cl)C(C)C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCN(C(C(=O)Nc2cc(CCC(=O)O)ccc2Cl)C(C)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45.0 mg (0.092 mmol) of tert-butyl 3-(4-chloro-3-{[4,4,4-trifluoro-3-methyl-2-(4-methylpiperidin-1-yl)butanoyl]amino}phenyl)propanoate (racemic diastereomer mixture) were dissolved in 0.1 ml of dichloromethane, and 0.35 ml of trifluoroacetic acid was added at RT. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 39.0 mg of the target product as a diastereomer mixture (97.9% of theory).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([CH:36](OC)[O:37]C)=[N:13][C:14]2[N:15]([C:21](=[O:35])[NH:22][C:23]3[CH:28]=[C:27]([O:29][CH:30]([CH3:32])[CH3:31])[C:26]([C:33]#[N:34])=[CH:25][N:24]=3)[CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1)[CH3:9])=[O:7])(=O)C.Cl>C1COCC1.O>[C:33]([C:26]1[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:28][C:23]([NH:22][C:21]([N:15]2[C:14]3[C:19](=[CH:20][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[CH2:5][OH:4])=[C:12]([CH:36]=[O:37])[N:13]=3)[CH2:18][CH2:17][CH2:16]2)=[O:35])=[N:24][CH:25]=1)#[N:34]
Reactant: COC(OC)c1nc2c(cc1CN(C)C(=O)COC(C)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(NC(=O)N2CCCc3cc(CN(C)C(=O)CO)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
To a solution of 2-(((8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)(methyl)amino)-2-oxoethyl acetate (intermediate 195, 378 mg, 0.682 mmol) in THF (1.7 ml) and water (1.7 ml) was added 37% aqueous HCl (1.12 mL, 13.64 mmol) at room temperature. The reaction mixture was stirred for 9.5 h at room temperature, quenched by the addition of saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was dissolved in DMF, filtered to remove insoluble impurities and purified by reversed phase preparative HPLC eluting with a gradient of MeCN and water (RP 5, H2O/MeCN 95:05 to 00:100 in 20 min). Fractions containing the product were collected, concentrated, diluted with water and basified with NaHCO3. The mixture was extracted with DCM (2×), dried using Na2SO4, filtered and concentrated. The resulting reddish solid was triturated in MeCN, filtered and dried to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:37]C(=O)C)[CH:10]=1.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:37][S:44]([CH:41]2[CH2:43][CH2:42]2)(=[O:46])=[O:45])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(CCN5CCOCC5)c4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(CCN5CCOCC5)c4)ccc32)c1)C1CC1

Procedure:
The compound was prepared from the compound of Example 139 using the procedures of Example 140 and cyclopropane sulfonyl chloride. 1H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 8.76 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.73 (d, 1H), 7.67-7.63 (m, 4H), 7.55 (s, 1H), 7.50-7.45 (m, 2H), 4.60 (t, 2H), 3.99-3.79 (m, 2H), 3.69-3.63 (m, 6H), 3.20-3.17 (m, 2H), 2.91-2.88 (m, 1H), 1.1-1.0 (d, 4H); LC-MS (ESI): Calculated mass: 604.67; Observed mass: 605.4 [M+H]+ (rt: 0.48 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH3:27])[CH:15]=3)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure used for the preparation of Intermediate 23, starting from ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol) and 4-chlorobenzene boronic acid (86 mg, 0.55 mmol) to give, after purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with petroleum ether 40-60° C.:EtOAc (19:1), the title compound (137 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>O>[C:1]1([NH:7][C:11]2[NH:12][N:8]=[N:9][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nnnn1-c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc(Nc2nnn[nH]2)cc1
Reaction time: 8 h

Procedure:
A suspension of 1-phenyl-1H-tetrazol-5-amine (38.63 g, 0.2397 mol) in xylenes (380 mL) was refluxed under nitrogen for 1.3 hours and allowed to cool. The suspension was stirred overnight. The mixture was chilled (+3° C.) for 2 hours, and the solids were filtered off. The filter cake was washed with PET ether and then dissolved in a solution of potassium hydroxide (20.1 g, 0.358 mol) in water (1.1 L). The mixture was filtered, and the filtrate was acidified by the dropwise addition of concentrated hydrochloric acid (46 mL, 0.55 mol). A precipitate formed. The solids were filtered off, washed with water (25 mL), and dried under house vacuum/air stream (40° C.), yield 35.0 g h(90%); mp=208°-209° C. (gas evol.)
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]([C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])=[C:11]3[NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:6]4[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:21][CH2:22]2)=[O:19])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(C#N)s4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N)CC4)c3c2)s1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(5-cyanothiophen-2-yl)-3-(cyclopropane carbonyl)quinolin-4-ylamino]cyclohexylcarbamate (24 mg, 0.047 mmol) was reacted with TFA (2 mL) to afford the desired product (13.2 mg, 32%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.25 (s, 1H), 8.54 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.85 (d, J=4.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 1H), 4.28 (s, 1H), 3.28-3.25 (m, 1H), 2.89-2.83 (m, 1H), 2.42 (d, J=12.8 Hz, 2H), 2.23 (d, J=12.2 Hz, 2H), 1.80-1.63 (m, 4H), 1.27-1.21 (m, 2H), 1.19-1.13 (m, 2H); ESI MS m/z 417 [C24H24N4OS+H]+; HPLC 95.1% (AUC), tR=10.32 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[O:4]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 71592 %

Procedure:
In a 3 L 3 neck flask with a mechanical stirrer, DMAP (11.5 g, 0.10 mmol) was added to a solution of 3-amino-thiophene-2-carboxylic acid methyl ester (105 g, 0.95 mmol) and in pyridine (750 mL). A solution of (BOC)2O (222 g, 1.02 mol) in pyridine (750 mL) was slowly added to the previous solution while the temperature was kept between 20 and 25° C. The mixture was stirred under nitrogen for 20 h. The reaction mixture was evaporated to dryness then triturated in 500 mL of MeOH at rat for 3 h then 30 min at 0° C. The suspension was filtered on a Buchner funnel and washed with cold ethanol. The white solid was dried to afford 175 g (70%) of 3-tert-Butoxycarbonylamino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(Br)cn2)C1
Yield: 27.3 %

Procedure:
Dissolve 5-bromo-2-fluoro-pyridine (5.20 g, 29.53 mmol), and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.50 g, 29.53 mmol) in acetonitrile (100 mL) and reflux with K2CO3 (8.90 g, 64.96 mmol) for 3 h. Filter the reaction mixture and wash with EtOAc (100 mL). Concentrate the filtrate and purify the resulting crude material by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 2.76 g (27%) of the title compound. LC-MS/ES m/z (81Br) 344.3 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:27](=[O:29])[CH3:28])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(O)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:27](=[O:29])[CH3:28])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(C)=O)cc1
Solvent: CCO
Product: CC(=O)Oc1ccc(N(Cc2ccc(O)cc2)C(C)=O)cc1
Yield: 87.8 %

Procedure:
The procedure of Preparation Example 9 was repeated, except that 400 mg of 4-[N-acetyl-N-(4-benzyloxybenzyl)amino]phenyl acetate was used in place of 4-[N-(4-benzyloxybenzyl)-N-methylsulfonylamino]phenyl methanesulfonate, and 6 ml of ethanol was used in place of dioxane. Thus, there was obtained 270 mg of 4-[N-acetyl-N-(4-hydroxybenzyl)amino]phenyl acetate.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Zn+].C(Cl)Cl.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33](Br)=[CH:34][CH:35]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].[NH4+].[Cl-]>C1COCC1>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH2:6][C:5]5[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=5[O:3][CH3:2])=[CH:34][CH:35]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: COc1ccccc1C[Zn+]
Reactant: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of (2-methoxybenzyl)zinc(II) chloride (4.44 mL, 0.5 M, 2.20 mmol) in THF and (DPPF)2PdCl2.CH2Cl2 (45 mg, 0.056 mmol) was stirred at room temperature for 20 minutes. To this, a slurry of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide (200 mg, 0.56 mmol) in THF (4 mL) was added and the reaction mixture was heated to 150° C. in a microwave reactor for 10 minutes. The resulting material was cooled to room temperature. Na2EDTA and saturated aqueous NH4Cl were added to the reaction and the mixture was stirred at room temperature for 30 minutes. The product was extracted using dichloromethane. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxybenzyl)pyridin-3-yl)cyclopropanecarboxamide (152 mg, 68%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1.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:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([C:5]2[O:6][C:2]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:3][CH:4]=2)[CH:14]=1)[C:10]#[N:11]
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: N#Cc1cc(F)cc(-c2ccc(Br)o2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)cc(-c2ccc(-c3ccccn3)o2)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 43.4 %

Procedure:
Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of 3-(5-bromofuran-2-yl)-5-fluoro-benzonitrile (180 mg, 86% purity, 0.59 mmol) and 2-trimethylstannylpyridine (193 mg, 0.80 mmol) in toluene (2.5 mL) under argon. The resulting solution was stirred at 110° C. for 48 h. After cooling to room temperature, the solvent was removed in vacuo. Flash chromatography (silica gel, 35–100% dichloromethane in hexane) afforded 67.7 mg (43%) of 3-fluoro-5-(5-(2-pyridyl)-2-furyl)-benzonitrile. 1H-NMR (CDCl3), δ (ppm): 8.64 (d, 1H), 7.76–7.83 (m, 3H), 7.66 (m, 1H), 7.24 (m, 2H), 7.19 (d, 1H), 6.92 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:34])[C:12](=[O:33])[C:13]([CH3:32])=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][C:16](=[O:21])[N:15]2[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1.[CH2:35]([O:42][CH2:43][CH2:44][CH2:45][CH2:46]O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C.O>[CH2:35]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][N:17]1[C:18](=[O:20])[C:19]2=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])[N:11]([CH3:34])[C:12](=[O:33])[C:13]([CH3:32])=[C:14]2[N:15]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)[C:16]1=[O:21])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(=O)Nc1cccc(-n2c(=O)[nH]c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Reactant: OCCCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(-n2c(=O)n(CCCCOCc3ccccc3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Yield: 77 %

Procedure:
Under argon atmosphere, to a suspension of N-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 89 (75.0 mg), 4-benzyloxybutyl alcohol 90 (25.0 μl) and triphenylphosphine (37.0 mg) in tetrahydrofuran (1.00 ml) was added diisopropyl azodicarboxylate (28.0 μl) with stirring under ice cooling. The mixture was stirred at the same temperature for 2 hrs, and 4-benzyloxybutyl alcohol (13.0 μl), triphenylphosphine (19.0 mg) and diisopropyl azodicarboxylate (14.0 μl) were added. The mixture was stirred at the same temperature for 1 hr, and water and ethyl acetate were added to allow partitioning. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:ethyl acetate=2:1→1:1) and thin layer chromatography (hexane:acetone=1:1) for further purification to give N-{3-[3-(4-benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 91 (74 mg, yield 77%) as a pale-yellow amorphous form.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[CH:8]=[C:9](I)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[OH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC12CC3(C)OC(C)(CC(C)(O3)O1)P2C1C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[CH:8]=[C:9]([C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([OH:22])[CH:24]=3)[CH:29]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C

Procedure:
In an embodiment, 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (1c) is reacted with 6-hydroxynaphthalen-2-ylboronic acid (compound (3a) in tetrahydrofuran in the presence of potassium phosphate tribasic, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane, and tris(dibenzylideneacetone)dipalladium(0) to provide 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4)).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[C:10]([O:31][C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=3)[C:11]3[C:16]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][N:14](COCC[Si](C)(C)C)[C:12]=3[N:13]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O.C(O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[C:10]([O:31][C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=3)[C:11]3[C:16]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:4]=[N:3]1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(C)c3)nc3c2c(-c2cccnc2)cn3COCC[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of N-{3-[(2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}prop-2-enamide (123 mg, 0.21 mmol) in DCM (10 mL) was added TFA (0.6 mL). The reaction solution was stirred at rt for 3 hrs. The volatiles were removed to give a residue. To the residue was added ethanol (20 mL), water (2 mL), and K2CO3 (142 mg) and the reaction mixture was stirred at rt for 1 hr. The volatiles were removed and water (10 mL) was added. The resulting solid was collected by filtration, washed with water (10 mL) and dried to give the title product (92.8 mg, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80 (br. s., 1H) 10.32 (br. s., 1H) 8.99-9.14 (m, 1H) 8.95 (d, J=1.51 Hz, 1H) 8.41 (dd, J=4.78, 1.51 Hz, 1H) 8.12 (d, J=7.55 Hz, 1H) 7.64 (br. s., 2H) 7.47 (s, 2H) 7.39 (dd, J=7.93, 4.91 Hz, 1H) 7.21 (br. s., 1H) 7.04 (br. s., 1H) 6.34-6.48 (m, 1H) 6.19-6.31 (m, 1H) 5.70-5.82 (m, 1H) 3.58 (br. s., 3H). m/z (APCI+) for C24H20N8O2 453.0 (M+H)+.