Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:48]=[CH2:49]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N+:22]([C:11]1[CH:10]=[C:9]([CH:49]=[CH:48][CH2:47][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:24])=[O:23]
Reactant: C=CCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C=CCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
19 mg of palladium acetate (II) was added to 5 mL of toluene solution containing 0.50 g of tert-butyl 4-bromo-2-nitrobenzoate, 50 mg of tri(o-tolyl)phosphine, 0.44 mL of allylbenzene and 0.46 mL of triethylamine, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 20 mg of palladium acetate (II) was added and the resulting mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=30:1] to obtain 0.31 g of tert-butyl 2-nitro-4-(3-phenyl-1-propenyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][S:6]1=[O:10].Cl[O-:16].[Na+]>O.[Ru](=O)=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][S:6]1(=[O:16])=[O:10]
Reactant: O=S1OCCN1Cc1ccccc1Cl
Reactant: [O-]Cl
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Product: O=S1(=O)OCCN1Cc1ccccc1Cl

Procedure:
contacting the N-(2-chlorobenzyl)-2-oxo-1,2,3-oxathiazolidine with ruthenium dioxide hydrate and aqueous sodium hypochlorite to give N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine,
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:11]2[CH2:12][CH2:13][CH:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)=[CH:17][CH:16]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: OB(O)c1ccc(Br)cc1
Product: CN1CCN(C2CCN(c3ccc(Br)cc3)CC2)CC1

Procedure:
1-[1-(4-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 1-methyl-4-piperidin-4-yl-piperazine (0.50 g, 2.7 mmol) and 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product isolated as a tan solid (0.077 g, 9%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.9 Hz, 2H), 6.79 (d, J=7.7 Hz, 2H), 3.72-3.65 (m, 2H), 2.85-2.35 (m, 14H), 2.00-1.90 (m, 2H), 1.73-1.60 (m, 2H). MS=338, 340 (MH)+. 51b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyri din-2-yl]-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(4-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (70.0 mg, 0.207 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as yellow solid (0.014 g, 13%). MP=237-240° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.6 Hz, 1H), 8.23 (d, J=7.7 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.01-6.95 (m, 3H), 6.66 (s, 1H), 3.70-3.62 (m, 2H), 3.10 (s, 3H), 2.73-2.32 (m, 11H), 2.30 (s, 3H), 1.98-1.90 (m, 2H), 1.77-165 (m, 2H). MS=546 (MH)+.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:24][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: Clc1nc2ccccc2[nH]1
Product: c1ccc(C(Nc2nc3ccccc3[nH]2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and benzhydrylamine by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 255-258° C.). MS(ES+) m/z 300 ([M+1]+, 100). 1NMR (DMSO-d6) δ 6.20 (d, 1H), 6.75-7.65 (m, 15H), 10.5 (s, 1H).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[N:23]([CH2:24]C(=C=O)OC)[N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[C:30]([O:33][CH2:34]C)(=[O:32])[CH3:31]>[Pd]>[NH2:11][C@@H:12]([CH2:17][CH2:18][C:19]1[N:23]([CH2:24][CH2:31][C:30]([O:33][CH3:34])=[O:32])[N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@H](CCc1nnnn1CC(=C=O)OC)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: COC(=O)CCn1nnnc1CC[C@H](N)C(=O)OC
Temperature: 24 °C
Reaction time: 4 h

Procedure:
To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-4-[1-(2-methoxy-carbonylethyl) tetrazol-5-yl]butyrate (0.233 g, 0.575 mmol) in ethyl acetate (25 ml) was added 10% Pd/C. (0.045 g). The resulting black mixture was degassed and then stirred at 24° C. for 4 hours under hydrogen. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to a colourless viscous oil that dried in vacuo over phosphorous pentoxide. There was thus obtained methyl (2S)-2-amino-4-[1-(2-methoxycarbonylethyl)tetrazol-5-yl]butyrate (0.146 g, 94%) as a colourless viscous oil. This was used in the next step without any further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH2:42].C(=O)([O-])[O-]>CN(C)C=O>[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH:42][C:29]1[CH:28]=[C:27]([CH2:26][N:23]2[CH2:22][CH2:21][N:20]([C:19]3[C:13]4[N:12]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=5)[NH:15][C:14]=4[CH:16]=[CH:17][CH:18]=3)[CH2:25][CH2:24]2)[CH:32]=[CH:31][C:30]=1[N+:33]([O-:35])=[O:34]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(CN2CCN(c3cccc4[nH]c(-c5ccc(C(C)(C)C)cc5)nc34)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (0.50 g, 1.03 mMol) in dimethylformamide (20 mL) was added glycine methyl ester hydrochloride (0.515 g, 4.10 mMol) and the reaction stirred at room temperature. To the homogeneous solution was added Argonaut MP carbonate resin (2.01 g, 3.06 mMol/g) and the mixture stirred for three hours. The mixture was filtered to remove the resin and the filtrate was then heated to sixty degrees and stirred overnight. Upon arrival the solution was cooled to room temperature and diluted with ethyl acetate (150 mL). After washing with water (3×50 mL) and brine (50 mL) the organics were dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator. Purification by flash column chromatography on silica gel using 20 to 25% ethyl acetate in dichloromethane as eluant yielded 470 mg (82% yield) of (5-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-2-nitro-phenylamino)-acetic acid methyl ester as a yellow-orange solid. 1H NMR (DMSO-d6): δ=12.69 (s, 1H), 8.43 (t, 1H, J=4 Hz), 8.04 (d, 2H, J=8.6 Hz), 7.76 (d, 1H, J=8.3 Hz), 7.55 (d, 2H, J=8.3 Hz), 7.03 (m, 2H), 6.90 (s, 1H), 6.78 (dd, 1H, J=8.8, 1.4 Hz), 6.50 (dd, 1H, J=7.1, 1.7 Hz), 4.32 (d, 2H, J=5.8 Hz), 3.72 (s, 3H), 3.58 (m, 6H), 2.64 (br s, 4H), 1.33 (s, 9H). LC/MS (Method A), rt=1.23 mins., purity=75.0%, calculated mass=556, [M+2H]+2/2=279, [M−H]−=555.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([CH3:11])=[CH:4][CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:15])=[O:9])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-methylpyridine-2-carboxylic acid (3.69 g, 21.51 mmol) was taken up in THF (100 mL)/MeOH (25 mL). A solution of TMS-diazomethane (21.5 mL, 43.0 mmol) was added and the resulting solution stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (2-20% EtOAc/hexanes) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]3[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=3)[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:25]N1C(=O)CCC1=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Cl:25][C:23]1[CH:22]=[N:21][N:20]([CH3:24])[C:19]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Yield: 58.9 %

Procedure:
To a stirred and cooled solution of Compound 119 (0.22 g, 0.63 mmol), in DMF (2.0 mL) was added N-chlorosuccinimide (0.168, 1.26 mmol). The reaction was stirred until the LCMS showed no starting material (2.5 hrs). The reaction mixture was poured into ice cooled water containing Na2S2O3 and NaHCO3 and the resulting solid was filtered, washed with ice-cooled water and dried in vacuo to afford a off-white solid 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea (0.14 g, 58%). LCMS m/z (%)=377 (M+H, 35Cl, 35Cl, 100), 379 (M+H, 35Cl, 37Cl, 59.4), 381 (M+H, 37Cl, 37Cl, 10.0). 1H NMR (400 MHz, DMSO-d6) δ: 9.76 (bs, 1H), 8.73 (bs, 1H), 8.56 (bs, 1H), 7.58 (s, 1H), 7.44-7.46 (dd, J=8.6, 2.03 Hz, 2H), 7.34-7.37 (dd, J=8.79, 2.7 Hz, 1H), 7.29 (dd, J=8.85, 2.07 Hz, 3H), 6.92-6.94 (d, J=6.78 Hz, 1H), 3.64 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O(C(C)(C)C)[K]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=3)[N:3]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc2nc(Cl)nc(N3CCCCC3)c2cc1OC
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(N3CCCCC3)c2cc1OC

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-4-piperidin-1-yl-quinazoline (3.08 g, 10.00 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 10.00 mmol, 1.0 equiv; commercially available), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.25 g, 0.40 mmol, 0.04 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.20 mmol, 0.02 equiv) and KOtert-Bu (1.35 g, 12.01 mmol, 1.2 equiv) in toluene (10 mL) was heated under Ar by microwave irradiation to 120° C. for 2 h. The crude reaction mixture was filtered through Hyflo Super Cel, a sat. solution of sodium chloride (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated by evaporation under reduced pressure and the residue purified on a Isolute flash NH2 chromatography column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.90 g (40%) of the title compound. MS (ISP): 472.4 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-ethylthio-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COc1cc(Cl)cc(C(=O)O)c1O

Procedure:
step a) 2-hydroxy-3-methoxy-benzoic acid (13) is chlorinated for example with N-chlorosuccinimide in acetic acid to yield 5-chloro-2-hydroxy-3-methoxy benzoic acid (14); step b) the methoxy group of compound (14) is reacted with hydrobromic acid in acetic acid to yield 5-chloro-2,3-dihydroxybenzoic acid (15);
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[I:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O>>[I:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C(O)c1ccncc1
Agent: O=C(O)c1ccc2ccccc2c1
Product: O=C(Nc1ccc(I)cc1)c1ccncc1

Procedure:
This compound was synthesized by the same procedure as for Example 15, except isonicotinic acid and 4-iodoaniline were used instead of 2-napthoic acid and 4-iodoaniline. M+325.1, mp 245-250° C.
Reaction SMILES: CO.C1COCC1.[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16](S(C)(=O)=O)=[N:15][C:14]=1[NH2:22])=[O:12])[CH3:9].[BH4-].[Na+]>O.C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C:13]1[S:17][CH:16]=[N:15][C:14]=1[NH2:22])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)nc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1scnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To 1 liter of a methanol:THF=1:1 mixed solvent solution containing 34.5 g of 4-amino-2-methanesulfonylthiazole-5-carboxylic acid ethyl ester, 10.4 g of sodium borohydride was added in small portions over a period of 20 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and then was poured into 8 liters of ethyl acetate and 4 liters of water. The organic layer was washed with 3 liters of water and 3 liters of saturated brine, and the aqueous layer was extracted with ethyl acetate again. The organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (19.3 g) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A mixture of the resulting thiourea (19.6 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.12 g, 42.3 mmol), and triethylamine (6.5 mL) in tetrahydrofuran (200 mL) was stirred at 50° C. for 3 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (15.4 g, 35.9 mmol, 71% in 2 steps).
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[C:12]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])([CH3:15])([CH3:14])[CH3:13].O>CS(C)=O>[C:6]([C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH:20][CH2:19][CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)cnc1F
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)cnc1NCCC(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of 6-fluoro-5-methylnicotinonitrile (Molekula 11370, 10 g, 73.4 mmol), beta-alanine tert-butyl ester hydrochloride (16 g, 88.1 mmol) and TEA (25.6 mL, 183.6 mmol) was prepared in DMSO (100 mL) under nitrogen, and then heated at 150° C. for 4 hours. The reaction mixture was cooled to 100° C. and water (100 mL) was added drop wise. The resulting mixture was stirred at RT for 2 hours, and then the precipitate was filtered off, washed with water and dried under reduced pressure to afford the title compound as a white solid (18 g, 94%). 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (1H, s), 7.56 (1H, s), 6.97 (1H, m), 3.59 (2H, m), 2.50 (2H, m), 2.02 (3H, s), 1.36 (9H, s).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1.C(OCC)(=O)C>[CH2:18]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:10]([NH:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:12])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
To a solution of 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (335.4 mg, 1 mmol) and triethylamine (404.8 mg, 4 mmol) in THF (5 mL) at −5° C., isobutyl chloroformate (143.5 mg, 1.05 mmol) was added dropwise. After 20 minutes, benzylamine hydrochloride (215.4 mg, 1.5 mmol) was added and the reaction mixture allowed to warm up to room temperature. The mixture was then diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated with silica gel and purified by column chromatography, eluting with 10-20% ethyl acetate in hexanes to give 2-(dibenzylamino)-3-(difluoromethoxy)-N-benzylpropanamide (367 mg, 86.5%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.56 (t, 1H), 7.17-7.34 (m, 15H), 6.35 (wt, 1H), 4.60 (dd, 1H), 4.43 (m, 3H), 3.95 (d, 2H), 3.68 (d, 2H) and 3.67 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][NH2:16])[N:8]=1>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][NH:16][C:7]([NH:8][CH3:9])=[N:6][C:5]#[N:4])[N:8]=1
Reactant: NCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CNC(=NC#N)NCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 24 h

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-(2-aminoethylthio)pyrimidine (0.25 g.), acetonitrile (5 ml.) and dimethyl (cyanoimido)dithiocarbonate (0.12 g.) was left at room temperature for 24 hours and then evaporated to dryness. The residue was dissolved in a 33% w/v solution of methylamine in ethanol, and the solution left at room temperature for 24 hours and then evaporated to dryness. The residue was recrystallised from ethanol to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(2-cyano-3-methylguanidino)-ethylthio]pyrimidine, m.p. 218°-221°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>O.C(#N)C>[OH:27][CH:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
Potassium carbonate (304 mg, 2.2 mmol) is dissolved in a minimum amount of water and 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) are added. The reaction is then heated at 80° C. for 3 days. After cooling to room temperature, the mixture is concentrated under reduced pressure, is taken up in ethyl acetate (15 mL) and washed with saturated aqueous ammonium chloride (2×10 mL) followed by water (10 mL). The organic phase is collected and dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is isolated as a colourless solid (80% yield).