Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([O-:38])=O)=[N:5]1.[K+].[N:40]1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CC(N(C)C)=O.O>[OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:33])([F:35])[F:34])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([NH2:40])=[O:38])=[N:5]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(=O)[O-])nn3CCO)CC4)c2)CC1
Reactant: O=C([O-])n1nnc2ccccc21
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3CCO)CC4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A suspension of potassium 1-(2-hydroxy-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.54 g, 2.69 mmol) in anhydrous DMA (40 mL) was treated with N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (1.03 g, 5.38 mmol) and with ammonium 1H-1,2,3-benzotriazol-1-ate (0.819 g, 5.38 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (1.32 g, 88% yield).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.56 g, 1.08 mmol) in dichloromethane (10 mL) and methanol (10 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (0.04 g, 0.21 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane gradient) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.41 g, 79%) as a light, yellow solid: HR-ES-MS m/z calculated for C22H27N4O5FCl [M+H]+ 481.1649, observed 481.1650; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.39-1.51 (m, 1H), 1.51-1.64 (m, 1H), 1.70-1.81 (m, 1H), 3.22-3.33 (m, 2H), 3.71-3.82 (m, 1H), 3.87 (dd, J=13.6, 7.5 Hz, 1H), 4.09 (dd, J=13.6, 3.8 Hz, 1H), 4.25 (d, J=18.5 Hz, 1H), 4.62 (d, J=18.5 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.88 (dd, J=10.8, 5.0 Hz, 1H), 4.93 (d, J=5.3 Hz, 1H), 5.03 (s, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.33 (td, J=8.3, 1.5 Hz, 1H), 7.49-7.61 (m, 3H), 10.77 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[O:15]
Reactant: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2N)cc1
Temperature: 40 °C
Reaction time: 13 h
Yield: 70.1 %

Procedure:
To a mixture of 4-methoxybenzyl (1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate (2.2 g) and methanol (11 ml) was added p-toluene sulfonic acid hydrate (1.2 g) at room temperature, followed by stirring at 40° C. for 13 hours. Further, p-toluene sulfonic acid hydrate (0.24 g) was added thereto, followed by stirring at 40° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid and diethyl ether were added to the residue. The aqueous layer was separated, and the organic layer was extracted with 1 M hydrochloric acid. The aqueous layer was combined, and sodium hydrogen carbonate was added thereto under ice-cooling to adjust the pH to about 7. The reaction mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-methoxybenzyl (1R,2S)-2-aminocyclopentanecarboxylate (1.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCOCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+].Br[C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:55][C:52]1[CH:53]=[CH:54][C:49]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:9][CH2:10]3)=[CH:6][CH:7]=2)=[N:50][CH:51]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reactant: Cc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)nc1
Temperature: 110 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20 mg, 0.00005 mol, prepared as example 238) in 1,4-dioxane (0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (0.2 mg, 0.0000002 mol), tri-tert-butylphosphine (0.12 mg, 5.8×10−7 mol), potassium fluoride (9.3 mg, 0.00016 mol) and 2-bromo-5-methylpyridine (0.012 g, 0.000073 mol), and the mixture was heated at 110° C. for 30 minutes. The reaction mixture was filtered and the filtrate was diluted with methanol. The product was isolated and purified with prep-HPLC. LC-MS: 425.2 (M+H+).
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20]>C(N(CC)CC)C>[CH2:4]1[CH2:3][CH2:2][CH:1]([O:7][C:8](=[O:14])[C@H:9]([CH2:10][C:11]([OH:13])=[O:12])[NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])[CH2:6][CH2:5]1
Reactant: CN(C)CCCN
Reactant: O=C(O)/C=C\C(=O)OC1CCCCC1
Solvent: CCN(CC)CC
Product: CN(C)CCCN[C@@H](CC(=O)O)C(=O)OC1CCCCC1
Yield: 73.2 %

Procedure:
In a manner analogous to that described in Example 1, 100 ml of triethylamine are added dropwise, with cooling, to 99.1 g (0.5 mol) of maleic acid-monocyclohexyl ester, and the mixture is reacted with 61.3 g (0.5 mol+20% excess) of 3-dimethylaminopropylamine for 1 hour at 80°-93° C. The reaction product is purified as described in Example 1 to yield 109.9 g (73.2% of theory) of the desired aspartic acid derivative having a melting point of 150°-152.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21](Cl)(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=1>>[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[N:8]=2)(=[O:22])=[O:23])=[C:16]([F:25])[CH:15]=1
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1cc(F)c(Br)cc1F

Procedure:
The title compound was prepared 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (22.3 mg) with purity >90%: MS (pos) m/z 471.2, 473.2.
Reaction SMILES: C(OCC)C.C(O)(=O)C(O)=O.[CH2:12]([O:15][CH:16]([O:20][CH2:21][CH:22]=[CH2:23])[C:17]([O-:19])=[O:18])[CH:13]=[CH2:14].[Na+]>O>[CH2:21]([O:20][CH:16]([O:15][CH2:12][CH:13]=[CH2:14])[C:17]([OH:19])=[O:18])[CH:22]=[CH2:23]
Reactant: C=CCOC(OCC=C)C(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C=CCOC(OCC=C)C(=O)O
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
100 g of diethyl oxide then a solution of 17.6 g (0.14 mole) of oxalic acid crystallised with two molecules of water in 62 g of water are introduced at ambient temperature and under agitation into an aqueous solution containing 29.1 g (0.15hole) of sodium diallyloxyacetate in 71 g of water. The biphasic medium obtained is agitated vigorously for 10 minutes then it is decanted. The ethereal phase is then dried over anhydrous sodium sulphate, filtered and finally concentrated to dryness under vacuum. In this way 24 g (0.14 mole) of pure diallyloxyacetic acid is obtained. This acid is in the form of an oil, it has a pka of 2.9 and it is soluble in water and in standard organic solvents such as diethyl oxide, dichloromethane; however, in aqueous solution, it hydrolyses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8]C.Br>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C(C)(C)CC(=O)O)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(C(C)(C)CC(=O)O)ccc1O
Temperature: 120 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
3-(3-Methyl-4-methoxyphenyl)-3-methylbutyric acid (11.1 g, 0.05 mol), acetic acid (22.3 g), and 48% hydrobromic acid aqueous solution (33.7 g, 0.2 mol) were mixed together, and stirred for 4 hours at 120° C. The mixture was cooled to room temperature, and the thus-obtained reaction solution was extracted with diethyl ether. The organic layer was washed with sodium chloride saturated aqueous solution, and then the solvent was removed by distillation to obtain 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid (10 g, yield: 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][C:11](Cl)=[CH:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCC1C=C(Cl)C=C(C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Product: CCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C
Yield: 97.9 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-6-methyl-2-n-pentyl-1,2-dihydropyridine (3.48 g, 11.61 mmol) in 220 mL of MeOH at 0° C. was added of lithium carbonate 0.857 g, 11.61 mmol) followed by 5% Pd/C. The mixture was placed under a positive pressure of hydrogen gas from a balloon, and the reaction progress was monitored by removing aliquots with a syringe, concentrating the aliquot in vacuo, and examining its 1H NMR spectrum. Upon completion, the mixture was filtered through Celite and evaporated. The residue was dissolved in ether (100 mL) and water (50 mL) was added, and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with 1M NaOH and brine. The organic phase was dried with potassium carbonate, filtered through Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 3.04 g (98%) of the product which was homogeneous by TLC analysis. 1H NMR (300 MHz) d 4.86 (br s, 1 H), 4.39-4.31 (m, 1 H), 2.02 (s, 3 H), 1.98-1.92 (m, 2 H), 1.91-1.28 (m, 21 H), 0.9-0.85 (t, 3 H); 13C NMR (75 MHz) 153.8 (s), 132.5 (s), 110.9 (s), 79.9 (s), 51.9 (s), 31.7 (s), 29.4 (s), 28.3 (s), 26.0 (s), 25.8 (s), 23.1 (s), 22.6 (s), 19.5 (s), 13.9 (s) ppm. FT-IR (neat) 2956, 2927, 2856, 1693, 1658, 1454, 1349, 1253, 1169, 1124, 1072 cm−1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCCc1cccnc1
Product: Clc1nc(Cl)nc(NCCc2cccnc2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 3-(2-aminoethyl)pyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:16]=1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:28]3[CH2:29][CH2:30][CH:25]([C:17]4[CH:16]=[N:15][C:24]5[C:19]([CH:18]=4)=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:26][CH2:27]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2ncc(C3CCNCC3)cc2c1
Product: c1ccc2ncc(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)cc2c1
Yield: 67.8 %

Procedure:
Beginning with 0.175 gm (0.83 mMol) 3-chloropropyl indol-4-yl ether and 0.177 gm (0.83 mMol) 4-(quinolin-3-yl)piperidine, 0.217 gm (68%) of the title compound were recovered as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][C:19](=O)[CH3:20]>>[CH2:1]([N:8]([CH3:16])[C:9]1[C:19]([CH3:20])=[CH:18][N:11]2[C:10]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)Cc1ccccn1
Reactant: CC(=O)CCl
Product: Cc1cn2ccccc2c1N(C)Cc1ccccc1
Yield: 34 %

Procedure:
This compound is obtained according to the same procedure as the compound of Preparation I, using the Tschitschibabin reaction and starting with 2.47 g of N-benzyl-N-methyl-N-[(pyridin-2-yl)methyl]amine and chloroacetone. 970 mg of a yellow oil are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].C([OH:15])C.C([O-])=O.[Na+]>O.C(O)=O>[OH:15][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4]
Reactant: CCO
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=C(CO)c1ccc(O)c(O)c1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A 1 liter reactor equipped with a reflux condenser and magnetic stirring bar was charged under argon with 45 g of 4-chloroacetyl-catechol of a purity of ca. 90%, 260 ml of ethanol, 130 ml of water, 38 g of sodium formate and 17 ml (˜21 g) of formic acid. The stirred mixture was heated under reflux (˜100° C.) for 24 hours. Under vacuum a part of the solvents was distilled off. The remaining solution of about 100 ml was acidified by addition of 35.5 g of conc. hydrochloric acid (37%) resulting in a pH of about 0.5. 200 ml of water were added and the mixture was refluxed for 10 minutes. Upon stirring over night without heating crystals separated. The slurry was filtered by suction and the crystals were washed with 50 ml of cold water. After drying over night at 70° C. at ˜20 mbar the yield of 4-hydroxyacetyl-catechol was 34.2 g with a purity of 89.2% corresponding to a yield of 82.6%. In the mother liquors additional 14% of the product was detected by analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:35]I>O1CCCC1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[N:8]([CH3:35])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Reaction time: 12 h
Yield: 74.4 %

Procedure:
To a solution of 5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid ethyl ester (0.5 g, 1.14 mmol) in tetrahydrofuran (25 mL) and dimethylsulfoxide (5 mL) cooled in a ice-water bath, NaH (50 mg, 1.26 mmol) and methyl iodide (0.08 mL, 1.26 mmol) were added. The reaction was continued at room temperature for 12 h, tetrahydrofuran was removed under vacuo, then dichloromethane (25 mL) was added and the organic phase washed with water (25 mL). The aqueous fraction was extracted with dichloromethane (2×20 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered in vacuo. Purification by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) provided 382 mg (74%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl-].[NH4+].CN(C)C=O.C(O)C.[N+:11]([C:14]1[S:18][C:17]([S:19][C:20]2[C:21]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1)([O-])=O>[Fe].O1CCCC1.O>[C:29]1([C:27]2[NH:26][C:22]3[N:23]=[CH:24][N:25]=[C:20]([S:19][C:17]4[S:18][C:14]([NH2:11])=[CH:15][CH:16]=4)[C:21]=3[CH:28]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ncnc3[nH]c(-c4ccccc4)cc23)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(Sc2ncnc3[nH]c(-c4ccccc4)cc23)s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
After adding 543 mg of iron powder, 1.06 g of ammonium chloride, 10 ml of dimethylformamide, 20 ml of ethanol and 5 ml of water to the 4-(5-nitro-2-thiophenylsulfanyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine synthesized in Production Example 162-1, the mixture was stirred at 90° C. for 2 hours, 30 ml of tetrahydrofuran was added, and then the mixture was returned to room temperature and filtered with celite, and ethyl acetate and water were added to the filtrate for liquid separation and extraction. The organic layer was dried over anhydrous sodium sulfate, filtered with plug cotton and concentrated to dryness to obtain 435 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Brc1ccccn1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccn1
Yield: 35 %

Procedure:
With 10.0 g of 5-chloro-1H-indol-2,3-dione and 25.3 g of bromo pyridine as starting materials, 5.03 g of the title compound (orange color solid) was obtained by a similar method to Step 34-3.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([S:24][CH:25]([CH3:27])[CH3:26])[N:21]=[C:20]([C:28]([OH:30])=O)[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].N.C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([S:24][CH:25]([CH3:27])[CH3:26])[N:21]=[C:20]([C:28]([NH2:33])=[O:30])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(SC(C)C)n3)CC2)c(Cl)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(SC(C)C)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 157.6 %

Procedure:
6-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(isopropylthio)pyrimidine-4-carboxylic acid (Example 180; 200 mg, 0.423 mmol), ammonia solution (2 M in MeOH, 0.43 ml, 0.846 mmol), TEA (0.06 ml, 0.423 mmol), and HATU (161 mg, 0.42 mmol) were combined in DMF (3 ml) and stirred at room temperature for 1 h. The reaction was diluted with EtOAc and water, and the organic portion was washed sequentially with 1 N HCl, saturated sodium bicarbonate, and brine. The organic portion was dried over sodium sulfate, filtered and concentrated to give an off-white solid (312 mg). The crude material was purified by preparatory HPLC using a gradient of 40-70% acetonitrile/water (0.1% TFA) over 14 minutes to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH:15]=[CH2:16])=[C:10]([NH2:17])[CH:9]=1.[BH4-].[Na+]>CO.Cl[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH2:15][CH3:16])=[C:10]([NH2:17])[CH:9]=1
Reactant: C=Cc1cc(Cl)c(-c2ccccc2Cl)cc1N
Agent: Cl[Cu]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(Cl)c(-c2ccccc2Cl)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
A mixture of 2′,6-dichloro-4-vinyl-[1,1′-biphenyl]-3-amine (500 mg, 1.9 mmol), CuCl (225 mg, 2.28 mmol) in MeOH (10 mL) at 0° C., NaBH4 (722 mg, 19 mmol) was added in portions and the resulting mixture was stirred at room temperature for 20 min. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (300 mg, 59.4% yield). ESI-MS m/z: 266.0[M+H]+.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:9]1(CCCN)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:2][CH2:3][CH2:4][CH2:5][CH:5]2[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: NCCCc1ccccc1
Product: c1ccc(NCCCC2CCNCC2)cc1

Procedure:
Starting materials: 1-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.), 3-phenylpropylamine (1.35 g, 1.0 eq.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[I-:25].[Na+].C1(C)C=CC=CC=1.CNCCNC>[Cu]I.O>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([I:25])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3C)CC2)c(C)c1
Yield: 59.5 %

Procedure:
To a mixture of (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (842 mg) described in Preparation Example 118, sodium iodide (650 mg) and copper(I) iodide (246 mg) were added toluene (2.2 mL) and N,N′-dimethylethylenediamine (1.62 mL), and the mixture was stirred with heating under reflux for 18 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the residue was purified by column chromatography (chloroform:methanol) to give the title compound (562 mg).