Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:30]([OH:32])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:50]([O:49][C:48]([NH:47][C@H:42]1[CH2:43][C@@H:44]([CH3:46])[CH2:45][N:40]([C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH:33][C:30]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:32])[CH2:41]1)=[O:54])([CH3:51])([CH3:52])[CH3:53]
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1=O
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methyl-3-oxopiperazin-1-yl)quinoline-2-carboxylic acid (0.012 g, 0.028 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.30 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound as a yellow solid (0.005 g, 20%). LCMS calc. for C39H46N8O6 [M+H]+: m/z=723.4. found: 723.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH3:13])[CH:6]=1.[Li]C(C)(C)C.[CH:19](=[O:22])[CH2:20][CH3:21]>CCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:9][C:10]=1[CH:19]([OH:22])[CH2:20][CH3:21]
Reactant: CCC=O
Reactant: CCCc1cccc(OCOC)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: CCCc1ccc(C(O)CC)c(OCOC)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a solution of 1-(methoxymethoxy)-3-propylbenzene (14.0 g, 77.7 mmol) in pentane (80 mL) at 0° C. was added tert-BuLi (55 mL, 93.2 mmol, 1.7 M in pentane) slowly. The resulting suspension was stirred at 0° C. for 1.5 h and then the precipitate was allowed to settle without stirring at 0° C. for 1.5 h. The supernatant was removed via a syringe and THF (180 mL) was added. To the thick slurry at 0° C. was added propionaldehyde (11.2 mL, 155.4 mmol, ran through basic alumina) slowly. The resulting solution was stirred at 0° C. for 1 h and then at room temperature for 12 h. About half of the solvent was removed in vacuo, the reaction solution was quenched with water, and most of the remaining THF was removed in vacuo. Extraction in EtOAc (2×200 mL) with 1:1 saturated NH4Cl/brine (100 mL) and flash chromatography with silica gel (gradient to 32% EtOAc/hexanes) provided the title compound as a colorless liquid (12.9 g, 70% yield): 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7.2 Hz), 0.96 (t, 3H, J=7.2 Hz), 1.61 (m, 2H), 1.82 (m, 2H), 2.37 (broad s, 1H), 2.55 (t, 2H, J=7.7 Hz), 3.50 (s, 3H), 4.82 (t, 1H, J=6.6 Hz), 5.22 (s, 2H), 6.84 (d, 1H, J=7.7 Hz), 6.91 (s, 1H), 7.23 (d, 1H, J=7.7 Hz); MS m/e 221 (M+H−H2O)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[CH:13]1([N:19]2[C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[CH:13]1([N:19]2[C:23]3([CH2:24][CH2:25][N:26]([C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:3])[CH2:27][CH2:28]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C1NCN(C2CCCCC2)C12CCNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2C1CCCCC1
Temperature: 25 °C
Yield: 50 %

Procedure:
Benzyl chloroformate (1.74 mL, 0.0116 mmol) was added dropwise at 0° C. to 1-cyclohexyl-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (prepared as described in J. Med. Chem. 1998, 41, 5084-5093); 1H NMR (DMSO-d6); δ1.11 (m, 2H); 1.24 (m, 4H); 1.58 (m, 4H); 1.77 (m, 4H); 2.38 (m, 2H); 3.32 (m, 3H); 4.21 (s, 2H); 9.35 (br s, 1H); 12.7 (br s, 1H); (3.59 g, 0.0116 mol) in pyridine (35 mL). The mixture was allowed to warm to room temperature and then evaporated. The residue was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash chromatography (5% methanol/dichloromethane) to give product as a white solid (2.15 g, 50%); 1H NMR (DMSO-d6); δ1.04 (m, 1H); 1.23-1.31 (m, 4H); 1.55-1.58 (m, 6H); 1.67 (d, J=10.4 Hz, 2H); 2.52 (m, 2H); 3.51 (m, 2H); 3.74-3.77 (m, 2H); 4.10 (s, 2H); 5.08 (s, 2H); 7.31-7.39 (m, 5H); 8.20 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Reactant: Clc1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Product: CC(C)(O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cc1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (example C.5 step 4) (198 mg, 0.5 mmol) and 2-(4-ethynyl-phenyl)-propan-2-ol (example D.4) (80 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (143 mg, 67%). MS (ISP) 428.3 [(M+H)+]; mp 148-150° C.
Reaction SMILES: [CH2:1]([C:5](O)([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br-].[Br:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:5]([Br:19])([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(O)(CCCC)c1ccc(F)cc1
Reactant: Br[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(Br)(CCCC)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 126.1 %

Procedure:
To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at −40 C. was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgSO4), and concentrated in vacuo. The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15 (dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, 1H), 9.45 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1.O=[C:32]1C2(COC3C=C4C(=CC2=3)CCO4)C2[C:34](=CC=CC=2)[N:33]1CC1OC(C(O)=O)=CC=1>>[CH3:32][N:33]([CH3:34])[C:28]([C:26]1[N:27]=[C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])[O:24][CH:25]=1)=[O:29]
Reactant: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Product: CN(C)C(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 13.1 and making non-critical variations using 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid to replace 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid, N,N-dimethyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide was obtained (3.0%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.09 (s, 1H), 7.27-6.86 (m, 4H), 6.50 (s, 1H), 6.40 (s, 1H), 5.08 (ABq, 2H), 4.82 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.29 (s, 3H), 3.06 (s, 3H), 2.97 (t, J=8.6 Hz, 2H); MS (ES+) m/z 431.8 (M+1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[CH2:14]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH:13]=[CH2:12]
Reactant: COc1ccc(C=O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C=O)ccc1OC
Yield: 88.5 %

Procedure:
Isovanillin (76 g) was dissolved in a stirred mixture of potassium carbonate (104 g) and acetone (450 mls) followed by the dropwise addittion of allyl bromide (67 g) over ca. 20 mins. The mixture was refluxed for 5 hours, cooled and filtered. The solvent was removed from the filtrate under reduced pressure and the residue was distilled under vacuum to yield 3-allyloxy-4-methoxybenzaldehyde (85 g), b.p. 137°-150° C. at 1.5 mbar.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]#[N:18])=[CH:10][C:9]=2[N+:19]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Sn]Cl.[CH2:25](O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)=O>[NH2:14][C:13]1[C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:25]=[N:19][C:9]=2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=1
Reactant: CCO
Reactant: N#Cc1cc([N+](=O)[O-])c(Nc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1cc(N)c2c(c1)ncn2-c1ccccc1
Yield: 64 %

Procedure:
To a stirred suspension of N-phenyl- 4-cyano-2,6-dinitroaniline (16.4 g, 57.8 mmol) and SnCl2, 2H2O (130.5 g, 0.58 mol) in abs. ethanol (300 ml) was added formic acid (90 ml) dropwise at ambient temperature. The reaction is exothermic. The reaction was allowed to proceed at ambient conditions overnight. The resultant mixture was rendered alkaline by addition of saturated, aqueous sodium carbonate and was filtered through Celite. The filtrate was extracted with dichloromethane. The organic extract was dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in cold ethyl acetate to leave the title product (8.65 g, 64%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[NH:9][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][CH2:11][C:8]1[N:9]=[CH:10][C:5]2[CH2:4][CH2:3][CH2:2][O:19][C:6]=2[CH:7]=1
Reactant: O=c1cc(COC2CCCCO2)[nH]cc1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1nc(COC2CCCCO2)cc2c1CCCO2
Reaction time: 0.17 h

Procedure:
To a solution of 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-one in 8 mL of tetrahydrofuran, 0.54 g of triphenylphosphine and 0.89 g of a 40% diethyl azodicarboxylate/toluene solution were added, and the mixture was stirred for 10 minutes. The solvent was distilled off under reduced pressure to obtain 7-((tetrahydro-2H-pyran-2-yloxy)methyl)-3,4-dihydro-2H-pyrano(3,2-c)pyridine as a brown oily substance.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:46]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)[CH:47]([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH2:46][CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: CC(C)Cc1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.34 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.2 g), 2-isobutylthiazole-4-carboxylic acid (0.13 g) and triethylamine (0.38 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.2 g.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:10][CH:9]=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.[Pd]>[C:30]([O:29][C:27]([NH:26][CH:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:1]=[O:4])[CH:9]=2)=[CH:9][CH:10]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Br)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(C=O)c2)cc1)C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 71 %

Procedure:
23 ml (45.9 mmol) of an aqueous 2M potassium carbonate solution and 1.77 g (1.50 mmol) of tetrakis palladium are introduced into a solution containing 6.64 g (15.3 mmol) of benzyl 3-(4-bromophenyl)-2-tert-butoxycarbonylaminopropionate and 3.45 g (23 mmol) of 3-boronic acid-benzaldehyde (Example 28b) in 75 ml of toluene. The reaction medium is heated at 80° C. for 20 h and, after a return to ambient temperature, extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with an 8/2 heptane/ethyl acetate mixture. 5.0 g of coupled product are obtained with a 71% yield.
Reaction SMILES: Br[C:2]1[O:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[C:12]1([C:3]2[C:4]3[C:9](=[O:10])[NH:8][CH:7]=[N:6][C:5]=3[O:11][C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:38][CH:39]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1[nH]cnc2oc(Br)c(-c3ccccc3)c12
Reactant: CC1(C)OB(c2ccc(OCCN3CCCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=c1[nH]cnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Temperature: 75 °C

Procedure:
Into a 16×100 mm vial sparged with argon was placed 6-bromo-5-phenylfuro[2,3-d]pyrimidin-4 (3H)-one 45 (250 mg, 0.859 mmol), 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)pyrrolidine (409 mg, 1.29 mmol), palladiumtetrakistriphenylphosphine (100 mg, 0.086 mmol), potassium carbonate (1.18 g, 8.59 mmol), DME (4 mL), and water (1 mL). The vial was capped and heated to 75° C. for 20 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:18])[CH3:17])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using acetyl chloride (39 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]acetamide (0.018 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:16]([NH:20][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Solvent: c1ccncc1
Product: Cc1nc(NC(C)(C)C)c2cccc([N+](=O)[O-])c2n1
Yield: 57.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-55, step-1 using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 300 mg, 1.34 mmol), and tert-butylamine (196 mg, 2.68 mmol) in pyridine (5 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.62-8.59 (d, J=8.1 Hz, 1H), 8.16-8.13 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.51 (t, J=7.8 Hz, 1H), 2.45 (s, 3H), 1.55 (s, 9H); MS (m/z): 261.20 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2c(c1)OCO2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of benzo[d][1,3]dioxol-5-ol (5.000 g; 36.20 mmol), and K2CO3 (5.503 g; 39.80 mmol) in anh. acetone (100 ml) was stirred at rt, under nitrogen, for 1 h. Iodomethane (28.258 g; 199.00 mmol) was then added, and the resulting mixture was heated at reflux, under nitrogen, for 20 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the filtrate was concentrated to dryness under reduced pressure. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 5-methoxybenzo[d][1,3]dioxole as a yellow oil. LC-MS (conditions A): tR=0.66 min.; no ionisation.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl.O>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([C:13](=[O:15])[CH3:14])[C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1cc(C)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1c(C)sc(C)c1C(C)=O
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of methyl 2,5-dimethyl-3-thiophene acetate (33.2 g, 0.18 mol) in CH2Cl2 (150 ml) was added to a solution of acetylchloride (15.5 ml, 0.216 mol) and tin (IV) chloride (23.2 ml, 0.198 mol) in CH2Cl2 (200 ml) at 0°-5° C. over a 15 minute period. The solution became a deep red color and was stirred at 0°-5° C. for two hours. H2O (200 ml) was added to the mixture, and the organic layer was separated, washed with saturated aqueous NaHCO3 (1×100 ml), dried over MgSO4, and treated with activated charcoal. The solvent was removed in vacuo to give the product (40.2 g, 97% yield) as an oil with crystallized slowly on standing; mp 68°-71° C.; IR (KBr) 1745 and 1650 cm-1 ; mass spectrum m/z 226 (M+); 1H NMR (CDCl3) δ 2.30 (s, 3H, thiophene-CH3), 2.47 (s, 3H, COCH3), 2.60 (s, 3H, thiophene-CH3), 3.67 (s, 5H, CH2CO2CH3).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cncc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cncc2cccc([N+](=O)[O-])c12
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To 45 ml of concentrated sulfuric acid was added 12.75 g of 4-methylisoquinoline (produced according to Tetrahedron, 1982, 38, 3347) under ice-cooling, and a solution of 9.02 g of potassium nitrate in 34 ml of concentrated sulfuric acid was added dropwise at a temperature not exceeding 0° C. After 30 minutes of stirring, the reaction mixture was poured in iced water containing aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to provide 12.0 g of light-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][CH2:68][CH2:69][O:70][CH3:71])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][CH2:68][CH2:69][O:70][CH3:71])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: COCCNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: COCCNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=551, obsd.=551).