Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([OH:10])[CH:5]=1)[CH3:2].C1C(=O)N([I:18])C(=O)C1>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:9]([I:18])=[CH:8][N:7]=[C:6]([OH:10])[CH:5]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOc1ccnc(O)c1
Solvent: CN(C)C=O
Product: CCOc1cc(O)ncc1I
Temperature: 80 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
To a mixture of 4-ethoxypyridin-2-ol (2.5 g, 17.97 mmol) in DMF (30 mL) was added NIS (4.04 g, 17.97 mmol). The mixture was stirred at 80° C. for 16 h. The mixture was concentrated and purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a yellow solid of 4-ethoxy-5-iodopyridin-2-ol (1.2 g, 4.30 mmol, 23.9% yield): 1H NMR (400 MHz, CD3OD) δ 7.70 (s, 1H), 5.92 (s, 1H), 4.15-4.10 (m, 2H), 1.48 (t, J=6.8 Hz, 3H); ES-LCMS m/z 265.8 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:23][C:22]4[C:17](=[N:18][CH:19]=[CH:20][C:21]=4[O:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH:35]5[CH2:37][CH2:36]5)=[O:33])=[CH:27][C:26]=4[F:38])[CH:16]=3)=[N:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:39]([O:41][C:42]([CH2:44][N:45]=[C:46]=[O:47])=[O:43])[CH3:40].CN(C=O)C>C1COCC1>[CH:35]1([NH:34][C:32](=[O:33])[NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:21]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:16]=[C:15]([C:12]5[N:13]=[CH:14][C:9]([CH2:8][N:5]6[CH2:6][CH2:7][CH:2]([NH:1][C:46](=[O:47])[NH:45][CH2:44][C:42]([O:41][CH2:39][CH3:40])=[O:43])[CH2:3][CH2:4]6)=[CH:10][CH:11]=5)[S:23][C:22]=34)=[C:26]([F:38])[CH:27]=2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)CN=C=O
Reactant: NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 343 (106 mg, 0.20 mmol, scheme 71) in THF (3 mL) was added ethoxycarbonylmethyl isocyanate (0.068 mL, 0.6 mmol) and stirred at RT for 3 h. To the mixture was added DMF (2 mL) and stirred for 1 h. The mixture was then concentrated, water was added to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 2-20%, (methanol/dichloromethane; SiliaFlash 10 g cartridge]. Title compound 425 was obtained as a white solid (79.5 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.73 (s, 1H), 8.54 (brd, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.59 (bd, 1H), 6.15 (d, J=8.0 Hz, 1H), 6.06 (t, J=8.0 Hz, 1H), 4.06 (q, J=6.4 Hz, 2H), 3.74 (d, J=6.50 Hz, 2H), 3.54 (s, 2H), 2.77-2.66 (m, 2H), 2.58-2.51 (m, 2H), 2.13-2.04 (m, 2H), 1.78-1.70 (m, 2H), 1.40-1.30 (m, 2H), 1.18 (t, J=6.8 Hz, 3H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 662.28 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:3]1.[CH2:17](Br)[CH:18]=[CH2:19].C(N(CC)CC)C>CN(C)C=O>[CH2:19]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:3][CH:2]1[CH3:1])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC1CN(c2ccc([N+](=O)[O-])cn2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
630 mg (2.72 mmol) of 3-methyl-1-(5-nitropyridin-2-yl)piperazine from Example 13.1 and 267 μl (3.09 mmol) of allyl bromide were dissolved in 10 ml of dimethylformamide. 1.2 ml (8.4 mmol) of triethylamine were then added dropwise to the solution. After the mixture had been stirred at room temperature for 1 hour, a further 65 μl (0.75 mmol) of allyl bromide were added dropwise to the reaction mixture, which was then stirred for a further hour. After that, a further 65 μl (0.75 mmol) of allyl bromide and 0.5 ml (3.6 mmol) of triethylamine were added drop-wise. The mixture was then stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was taken up in water and this solution was made alkaline using a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness, with 707 mg (90% of theory) of the title compound being obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9]2)#[N:5].C([O-])([O-])=O.[K+].[K+]>CO.ClCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]2[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4](=[N:2][OH:3])[NH2:5])[CH:7]=3)[C:12]2=[O:16])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C#N)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Hydroxylamine hydrochloride (183 mg, 2.64 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(6-cyano-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (185 mg, 0.440 mmol) and K2CO3 (365 mg, 2.64 mmol) in MeOH (20 mL) and the mixture was stirred at room temperature for overnight. The mixture was diluted with dichloromethane (60 mL), washed with aqueous ammonium chloride (saturated, 1×20 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 5-(2-(4-fluorophenyl)-6-(N′-hydroxycarbamimidoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (200 mg, 0.441 mmol) as an off white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)#[CH:17].C(N(CC)CC)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[C:2]([C:17]#[C:16][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1)=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: C#CC12CC3CC(CC(C3)C1)C2
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Next, 125 g of dimethyl 5-bromoisophthalate (458 mmol), 1.1 g of triphenylphosphine (4.19 mmol), 0.275 g of copper iodide (1.44 mmol), 64.26 g of 1-ethynyladamantane (401 mmol), 375 mL of dehydrated triethylamine, 200 mL of dehydrated pyridine, 0.3 g of dichlorobis (triphenylphosphine) palladium (0.427 mmol) and a stirrer were charged in a 1 L recovery flask and agitated at 100° C. for one hour. After reaction solution was filtered, solvent was removed from the reaction solution under reduced pressure. Solid thus obtained was washed with 1 L of ion-exchange water and then with 1 L of 2 mol/L hydrochloric acid aqueous solution, followed by drying under reduced pressure, thus obtaining 121.5 g of 1-(3,5-bis(methoxycarbonyl)phenyl)-2-(1-adamantyl)ethyne (344.9 mmol; yield: 86.0%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=[C:19]3[N:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=1[OH:43]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=[C:19]3[N:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[O:43][C:37]2[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:36]=2[CH3:35])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cnc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2c1
Reactant: Cc1cccc(C)c1O
Product: CCOc1cnc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3c(C)cccc3C)n(-c3ccccc3)c2c1

Procedure:
The title compound was prepared from the compound of example 54, step 7, (290 mg, 598 μmol) and 2,6-dimethylphenol analogously as described in example 1, step 6.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O.O>C1(C)C=CC=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[N:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=Cc1ccccn1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1N=Cc1ccccn1

Procedure:
27.6 g of o-nitroaniline and 21.4 g of 2-pyridine aldehyde are heated in 200 ml of toluene for 10 hours, and the water formed is collected by means of a water separator. 500 ml of diethyl ether are then added to the solution, and the crystals which precipitate are filtered off with suction.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:5]=1[CH2:11][N:12]([CH2:23][C:24]([O:26][CH3:27])=[O:25])S(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO>[CH3:27][O:26][C:24]([C:23]1[N:12]=[CH:11][C:5]2[C:4]([C:3]=1[OH:2])=[CH:9][CH:8]=[CH:7][C:6]=2[I:10])=[O:25]
Reactant: COC(=O)CN(Cc1c(I)cccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(I)cccc2c1O
Yield: 42 %

Procedure:
To a solution of crude 3-Iodo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-benzoic acid methyl ester (37.8 g) in methanol (220 mL) was added a solution of NaOMe (30 wt %) in methanol (40 mL) with stirring. After stirring for 18 h at ambient temperature the mixture was concentrated in vacuo. To the residue was added 1 N hydrochloric acid (200 mL) and the mixture was extracted with hot ethyl acetate (1×300 mL). The organic phase was then washed with concentrated aqueous NaHCO3 solution (3×200 mL), dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give the title compound as a tan solid (10.1 g); MS-(+)-ion: M+1=329.8.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.CCCCCC.C(Cl)Cl>CO.O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (22.3 g, 42.7 mmol) was suspended in methanol (223 mL, 10 mL/g), and a solution of pTsOH.H2O (4.1 g, 21.35 mmol) in water (22.3 mL) was added. The mixture was stirred at ambient temperature for 18 hrs, during which all solids dissolved to give a colorless, clear solution. The solution was concentrated and extracted with ethyl acetate (2×300 mL). The organic solution was washed with sodium bicarbonate, dried over MgSO4. After filtration, the filtrate was concentrated, and co-evaporated with heptane to give a foaming solid. To this solid was added hexane-CH2Cl2 (1:1, 100 mL) and the mixture was stirred for 30 min. A white solid formed, which was filtered, washed with hexane. The solid was recrystallized from hexane-AcOEt to give N-((R)-2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as white crystals, 13.57 g (65.9%), after drying at 60° C. vacuum oven for 3 days. A second crop of 5.05 g was obtained from the mother liquor, after recrystallization from the same solvent system. The total yield was 18.62 g (90.4%): m.p. 89–90° C. (Form II). The combined crystals were ground with a set of mortar and pestle to fine powder, and dried at 60° C. in a vacuum oven for 3 days: m.p. 117–118° C. (Form I); [α]=−2.05° (c=1.12, methanol); Analysis: Calcd. For: C16H14F3I1N2O4: C, 39.85; H, 2.93; N, 5.81; F, 11.82, I, 26.32. Found: C, 39.95; H, 2.76; N, 5.72; F, 11.71; I, 26.53. 1NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.69 (s, 1H), 7.54 (dd, 1H, J=10.9, 1.5), 7.32–7.38 (m, 2H), 7.17 (dd, 1H, J=16.8, 9.0), 6.61–6.66 (cm, 1H), 4.82 (bs, 1H), 4.58 (bs, 1H), 3.84–3.85 (m, 1H), 3.71–3.64 (cm, 2H), 3.33 (2H, partially hidden by HDO).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:12]=2[CH3:13])=[CH:4][C:3]=1[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>ClCCl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:12]=2[CH3:13])[CH:4]=1
Reactant: Cc1c(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: Cc1c(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cnn1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (400 mg), tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (371 mg), tris(dibenzylideneacetone)dipalladium (49 mg), tricyclohexylphosphine (30 mg) and potassium phosphate (389 mg, 1.83 mmol) in dioxane (2.4 ml) and water (0.4 ml) were stirred at 100° C. for 3 h under argon. The reaction mixture was filtered and purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 micron silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/min) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (214 mg). NMR Spectrum: (DMSOd6) 1.43 (s, 9H), 1.83-1.92 (m, 4H), 2.42 (s, 3H), 2.95 (bs, 2H), 4.02-4.14 (m, 2H), 4.39-4.48 (m, 1H), 7.42-7.49 (m, 2H), 7.66 (s, 1H), 7.67 (bs, 2H), 7.79 (d, 1H), 7.84 (d, 1H), 8.22 (d, 1H), 8.29 (d, 1H); Mass spectrum: M+H+ 475 TFA (1 ml) was added to a solution of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (126 mg) in dichloromethane (1 ml). The solution was stirred at 25° C. for 1 hour. After evaporation of the solvents, the crude mixture was diluted in dichloromethane and 7N methanolic ammonia was added. After evaporation of the solvents, the residue was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane and 10 to 25% methanolic ammonia (7N) in dichloromethane. The solvent was evaporated to dryness and triturated in acetonitrile to afford 3-(1,3-benzoxazol-2-yl)-5-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (66 mg). NMR Spectrum: (DMSOd6) 1.79-1.87 (m, 2H), 1.90-2.01 (m, 2H), 2.40 (s, 3H), 2.65-2.75 (m, 2H), 3.07-3.15 (m, 2H), 4.23-4.33 (m, 1H), 7.40-7.49 (m, 2H), 7.65 (s, 1H), 7.67 (bs, 2H), 7.79 (dd, 1H), 7.84 (dd, 1H), 8.21 (d, 1H), 8.29 (d, 1H); Mass spectrum: M+H+ 375.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>CN(C)C=O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 180 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
2-amino-4-fluorobenzoic acid (100 g, 0.64 mol) and formamide (154 mL, 3.87 mol) were mixed with a catalytic amount (1 mL) of N,N-dimethylformamide. The mixture was heated to 180° C. and further stirred for 14 hours. The mixture was cooled to room temperature, and distilled water (1000 mL) was added thereto. The mixture was stirred for 30 min and filtered to obtain the title compound (86 g, 81.3%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[C:18](=[CH:22][O:21][CH2:19][CH3:18])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2CCN(C(C)=O)CC2)cc1F
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCN(C(C)=O)CC2)cc1F

Procedure:
A solution of 2.68 g (7.57 mmol) ethyl 4-(1-acetyl-4-piperidinyl)-2,5-difluoro-β-oxobenzenepropionate in 16 ml of acetic anhydride and 1.9 ml of triethyl orthoformate was refluxed 1.25 hours. The title compound was isolated as a syrup after evaporation under vacuum in an oil bath at 80° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[N:19]#[C:20][NH2:21].[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:20]([NH2:21])=[NH:19]
Reactant: Cc1cccc(C)c1N
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=N)N

Procedure:
To 36 g. (0.315 mole) of 2,6-dimethylaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g. (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml. of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 2,6-dimethylphenylguanidine.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (36 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 32 mg, 75%).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:20][C:21]1[CH:25]=[C:24]([NH:26][C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=O)[N:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:22]=1.[OH-].[Na+]>C(OCC)(=O)C.CO.O>[CH3:20][C:21]1[C:25]2[C:29](=[O:31])[C:28]3[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:26][C:24]=2[N:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:22]=1
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccccn2)n1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
A mixture of methanesulfonic acid (120 mL, 0.84 mol) and phosphorus pentoxide (24.0 g, 0.17 mol) was heated at 100° C. The mixture was stirred thoroughly at the same temperature, with the gradual addition of powdery 2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (24.0 g, 82 mmol). The reaction mixture was heated and stirred at the same temperature further for 15 minutes. The mixture was allowed to cool to room temperature, and water was added thereto. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (chloroform). The crystals thus obtained we dissolved in a mixture of ethyl acetate (300 mL) and methanol (300 mL) under heating, and heated under reflux for 30 minutes after the addition of activated carbon (2.5 g). The hot solution was filtered, and the solvents were evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (15.1 g, 67% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].Cl.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1>>[Cl:5][CH2:6][C:7]([C:17]1[CH:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=1[CH3:11])=[O:8]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(=O)CCl)c1
Temperature: 13.5 °C
Reaction time: 2 h

Procedure:
293.2 g [2.2 mol] of aluminum chloride are metered over the course of about 75 minutes into a mixture of 800 g p-xylene and 226 g [2 mol] of chloroacetyl chloride at 12-15° C. The reaction mixture is stirred at 12-15° C. for 2 hours, allowed to reach room temperature, stirred at room temperature for 30 minutes and then poured into 3000 ml of ice-water with 70 g of conc. hydrochloric acid. The cloudy organic phase is separated off, and the aqueous phase is extracted three times with 300 ml of ethyl acetate each time, and the combined organic phases are extracted twice with 200 ml of water each time and once with 100 ml of saturated aqueous NaCl solution. The organic phase is dried, evaporated and distilled as far as a bath temperature of 70° C./1 mbar. 363.6 g of yellowish oil result and, according to GC, contain 97.2% target product (96.8% of theory).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH:20]=O)=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:20]([CH2:19][O:18][C:17]3[CH:22]=[CH:23][C:14]([C:13]([F:12])([F:24])[F:25])=[CH:15][CH:16]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCOc1ccc(C(F)(F)F)cc1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2COc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (3.880 mmol) and (4-trifluoromethyl-phenoxy)-acetaldehyde (0.792 g; 3.880 mmol) afforded 3-ethyl-1-iodo-8-(4-trifluoromethyl-phenoxymethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.73 min.; [M+H]+=452.12 g/mol.