Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([CH3:16])=[O:15])[C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].S(OCC)(O[CH2:21][CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([CH3:16])=[O:15])[C:5]=1[C:6]([O:8][CH2:21][CH3:22])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1C(=O)O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(NC(C)=O)cccc1C(C)=O
Temperature: 0 °C
Yield: 91 %

Procedure:
The mixture of 4.0 g of 2-acetyl-6-acetaminobenzoic acid, 3.1 g of diethyl sulfate and 2.8 g of potassium carbonate in 40 ml of acetone was allowed to react under stirring under refluxing for 5 hours. After the reaction was over, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and concentrated to obtain 4.1 g of ethyl 2-acetyl-6-acetaminobenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:12]2[S:8][C:9]([C:13]3[N:18]=[C:17]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH:16]=[CH:15][CH:14]=3)=[N:10][CH:11]=2)[CH:3]=1
Reactant: c1cnc(-c2cccc(-c3nccs3)n2)nc1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cnc(-c2cccc(-c3ncc(-c4cccnc4)s3)n2)nc1

Procedure:
Under argon, 79 mg (0.50 mmol) of 3-bromopyridine, 120 mg (0.50 mmol) of 2-[6-(1,3-thiazol-2-yl)pyridin-2-yl]pyrimidine (cf. step 1), 326 mg (1.0 mmol) of cesium carbonate and 8 mg (0.01 mmol) of [(t-Bu)2P(OH)]2PdCl2 (“POPd”) in 10 ml of N,N-dimethylformamide were stirred at 120° C. for 16 hours. For work-up, the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water and the organic phase was dried, concentrated under reduced pressure and purified by column chromatography on silica gel RP-18 (mobile phase: water/acetonitrile/formic acid). This gave 28 mg (18% of theory) of 2-{6-[5-(pyridin-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl.CCOC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 64 h
Yield: 81.2 %

Procedure:
Methyl anthranilate (110 g, 0.73 mol) was dissolved in dichloromethane (1 liter) at 0° C. and triethylamine (115 ml, 0.8 mol) was added. Tosyl chloride (133 g, 0.745 mol) was added portionwise at 0° C. The reaction mixture was stirred for 30 min at 0° C. and 64 h at room temperature. The mixture was reduced in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with 5% KHCO3 (aq) solution, 1N HCl solution and brine, dried, filtered and concentrated in vacuo. The residue was crystallised from EtOAc/hexane to yield the title compound (181 g, 81%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1.[H][H].[CH3:15][N:16]([CH3:31])[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[C:22]2[S:27](Cl)(=[O:29])=[O:28]>COCCOC>[CH3:15][N:16]([CH3:31])[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[C:22]2[S:27]([NH:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1)(=[O:29])=[O:28]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1nc(Cl)ncc1N
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(Cl)ncc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.1 g) was added to a solution of 5-amino-2-chloro-4-methoxypyrimidine (0.159 g) in 1,2-dimethoxyethane (10 ml). When evolution of hydrogen had ceased, 5-dimethylamino-1-naphthalenesulphonyl chloride (0.336 g) was added and the solution was stirred for 2 hours. Volatile material was then removed by evaporation. The residue was purified by elution with ethyl acetate/hexane/acetic acid (0-20% ethyl acetate, 0.1% acetic acid) through a silica gel Mega Bond Elut column to give 5-dimethylamino-N-(2-chloro-4-methoxy-5-pyrimidinyl)-1-naphthalenesulphonamide (0.067 g) as an oil; 1H NMR (d6 -DMSO): 2.85 (s, 6H), 3.39 (s, 3H), 7.3 (d, 1H), 7.6 (t of t, 2H), 8.08 (d, 1H), 8.25 (s, 1H), 8.30 (d, 1H), 8.5 (d, 1H), 10.42 (s, 1H); mass spectrum (+ve FAB, dichloromethane/NBA): 393 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16]>O>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(C)=O)ccc1O
Solvent: O
Product: COc1cc(C(C)=O)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 40 ml of nitric acid (d=1.41) and 40 ml of water was gradually added while cooling (below 7° C.) and stirring 25.0 g of 4'-hydroxy-3'-methoxyacetophenone. After stirring for 0.5 h at 0° C. the product was filtered, washed first with diluted nitric acid (1:1) and then with water. Yield 24.0 g (75%). The 1H-NMR-spectrum of the product was in accordance with the structure alleged.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1OCCCC(N1[C:19]2[C:14](=[C:15](C3C=NN(CC(OCC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13]CC1)=O.OCCCC(N1C2C(=C(C3C=NN(CC(OCC)=O)C=3)C=CC=2)CCC1)=O.[OH:64][CH2:65][CH2:66][CH2:67][C:68]([N:70]1[C:79]2[C:74](=[C:75]([C:80]3[CH:81]=[C:82]([CH:97]=[CH:98][CH:99]=3)[CH2:83][O:84][C:85]([NH:87][CH2:88][CH2:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])=[O:86])[CH:76]=[CH:77][CH:78]=2)[CH2:73][CH2:72][CH2:71]1)=[O:69].ClC1C=C(Cl)C(Cl)=CC=1O.C1(C)C(O)=CC=CC=1>>[C:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:64][CH2:65][CH2:66][CH2:67][C:68]([N:70]1[C:79]2[C:74](=[C:75]([C:80]3[CH:81]=[C:82]([CH:97]=[CH:98][CH:99]=3)[CH2:83][O:84][C:85]([NH:87][CH2:88][CH2:89][C:90]([O:92][C:93]([CH3:96])([CH3:94])[CH3:95])=[O:91])=[O:86])[CH:76]=[CH:77][CH:78]=2)[CH2:73][CH2:72][CH2:71]1)=[O:69]
Reactant: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cc(Cl)c(Cl)cc2Cl)cn1
Reactant: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(-c2cccc3c2CCCN3C(=O)CCCO)c1
Agent: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCO)cn1
Agent: Cc1ccccc1O
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Product: Cc1ccccc1OCCCC(=O)N1CCCc2c(-c3cccc(COC(=O)NCCC(=O)OC(C)(C)C)c3)cccc21

Procedure:
The title compound was prepared using a procedure analogous to ethyl 2-(4-(1-(4-(2,4,5-trichlorophenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate except that ethyl 2-(4-(1-(4-hydroxybutanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate was replaced with tert-butyl 3-((3-(1-(4-hydroxybutanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyloxy)carbonylamino)propanoate and 2,4,5-trichlorophenol was replaced with o-cresol. LCMS, [M+H]+=587.3.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([N:18]([CH2:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:26]
Reactant: COc1ccc(CN)cc1
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: COc1ccc(CN(C(=O)NCCCl)C2OC[C@H](O)[C@H](O)[C@H]2O)cc1
Yield: 74.8 %

Procedure:
3.0 g of L-arabinose, 3.0 g of p-methoxybenzylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 31-(1). 5.6 g of 1-(2-chloroethyl)-3-(p-methoxybenzyl)-3-(L-arabinopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.CCN(CC)CC.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>CN(C1C=CN=CC=1)C.O>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:8]2[C:9]3[CH:10]=[N:11][C:2]([NH:1][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:3][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 7 %

Procedure:
To a stirred solution of 7-amino-4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidine (J Med Chem, 1995;38:3780) (140 mg, 0.46 mmol), DMAP (14 mg) and Et3N (excess, 2.0 mL) at 0° C. under N2 was added acryloyl chloride (4.8 mol eq., 182 μL) dropwise over 4 hours. The reaction was then stirred at 20° C. diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure before being chromatographed on silica gel eluting with MeOH/CH2Cl2/EtOAc (5:45:50), to give N-[4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidin-7-yl]-acrylamide (12 mg, 7%) as a cream powder, mp (CH2Cl2/hexane) 215-220° C. (dec).
Reaction SMILES: [CH3:1][NH2:2].C([O-])([O-])=O.[Na+].[Na+].[Br:9][CH2:10][CH2:11][C:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>O.C1(C)C=CC=CC=1>[BrH:9].[C:16]1([C:12]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:11][CH2:10][O:14][C:13]2=[CH:1][NH2:2])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN
Reactant: O=C(Cl)C(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Br
Product: NC=C1OCCC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a mixture of 35% aqueous methylamine (100 g, 1.13 mol) and Na2CO3 (106 g, 1 mol) in H2O (1000 ml) and toluene (800 ml) was added dropwise 4-bromo-2,2-diphenylbutyroyl chloride (337.5 g, 1.13 mol) in toluene (200 ml), while the temperature was maintained between 0 and 15° C. The mixture was allowed to warm to room temperature and the precipitate was collected by filtration. The solid precipitate was then taken up into CHCl3the solution was dried (MgSO4), and the solvent was removed in vacuo. The residue was crystallized from i-BuCOMe (isobutylmethylketone) to afford pure N-(tetrahydro-3,3-diphenyl-2-furylidene)methylamine hydrobromide (223 g, 67%), mp 159-161° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3[CH:28]([F:30])[F:29])[N:16]=[C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:14]=2)[CH2:8][CH2:7]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.O>CN(C)C=O>[CH:43]1([NH:47][CH2:2][C:3]([NH:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[CH:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]4[CH:28]([F:30])[F:29])[N:16]=[C:15]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:14]=3)[CH2:8][CH2:7]2)=[O:4])[CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCC1
Reactant: O=C(CBr)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNC1CCC1)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]acetamide (100 mg) was suspended in dimethylformamide (2 mL), and potassium carbonate (30 mg) and cyclobutylamine (60 μL) were added thereto, followed by stirring at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel chromatography (hexane:ethyl acetate=40:60-10:90) to obtain N2-cyclobutyl-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]glycinamide (79 mg).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:26][NH:27][CH3:28].CC(=O)CC>C(OCC)(=O)C.CCCCCC>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]([CH3:28])[CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CNC
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N(C)C)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), an aqueous solution of dimethylamine (50%, 1.0 ml) and 2-butanone (10 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was concentrated, the residue obtained was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-dimethylamino-5-[3-(2-methoxyphenoxy)propyl]oxazole was obtained as an oil (348 mg, 90%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction. Crystallization from acetone-hexane gave pale yellow prisms. Melting point 67-68° C.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH2:32]([NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH3:33]
Reactant: CCN(C[C@@H](N)c1cc(F)c(F)cc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(F)cc1F

Procedure:
Compound 58 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [391 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.13 (s, 1H), 9.02 (d, 1H), 8.57 (s, 1H), 8.38 (t, 1H), 8.18 (s, 1H), 7.66 (dd, 1H), 7.53 (td, 1H), 5.71 (s, 1H), 3.15 (dd, 1H), 2.95 (dd, 1H), 2.67-2.55 (q, 2H), 0.98 (t, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](O)=[O:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:16]=[C:11]([C:10]([NH:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([NH:2][C:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])[CH2:4][CH2:5]2)=[O:27])[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[N:13][CH:14]=1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)c3ccccn3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(trans-4-amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (250 mg, 0.666 mmol) in dimethylformamide (5 ml) and triethylamine (278 μl, 2.0 mmol) was treated with 2-pyridine carboxylic acid (90 mg, 0.73 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (141 mg, 0.73 mmol) and 1-hydroxybenzotriazole (99 mg, 0.73 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml) and the aqueous phase was extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure to give the title compound (175 mg) as a white solid.
Reaction SMILES: [BH4-].[CH2:2]([C:9]1[N:10]([CH3:15])[C:11]([SH:14])=[N:12][N:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=2)=[C:19]([O:37][CH2:38][CH2:39][CH3:40])[CH:18]=1>O1CCCC1.C(O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][CH2:21][C:20]2[CH:35]=[CH:36][C:17]([S:14][C:11]3[N:10]([CH3:15])[C:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:13][N:12]=3)=[CH:18][C:19]=2[O:37][CH2:38][CH2:39][CH3:40])=[CH:24][CH:25]=1)[CH3:34]
Reactant: CCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Reactant: CCCCCCCc1nnc(S)n1C
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCc1nnc(Sc2ccc(CNc3ccc(CC(=O)OCC)cc3)c(OCCC)c2)n1C
Reaction time: 8 h

Procedure:
2.647 g (6.62 mmol, 3 eq) of resin-supported borohydride and 30 mg (0.06 mmol, 0.03 eq) of bis(bipyridine)dibromonickel (II) are added to a solution of 0.706 g (3.31 mmol, 1.5 eq) of 5-heptyl-4-methyl-4H-[1,2,4]-triazole-3-thiol in 10 ml of tetrahydrofuran/ethanol 5/5. To the suspension obtained there is added a solution of 100 mg (0.22 mmol, 1 eq) of ethyl [4-(4-iodo-2-propoxybenzylamino)phenyl]acetate in 10 ml of tetrahydrofuran/ethanol 5/5. The reaction mixture is stirred overnight under reflux. After returning to room temperature, the reaction medium is filtered, concentrated and then chromatographed on silica gel (heptane/ethyl acetate 40/60). After evaporation of the solvents, 0.750 g (63%) of the expected compound is recovered.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH3:10])[C:4](=[O:11])[CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:6](=[O:8])[N:5]([CH2:9][CH3:10])[C:4](=[O:11])[CH:3]=1
Reactant: CCn1c(=O)cc(Cl)[nH]c1=O
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.7 %

Procedure:
A mixture of 6-chloro-3-ethylpyrimidine-2,4(1H,3H)-dione (0.5 g), 4-bromomethyl-2'-(N-trityltetrazol-5-yl)biphenyl (1.68 g) and potassium carbonate (0.48 g) in DMF (20 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (1.3 g, 70%).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[I:1][C:2]1[C:7]([O:8][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1I
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccnc2I)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
2-Iodo-pyridin-3-ol (50 mg, 0.226 mmol), K2CO3 (62 mg, 0.452 mmol) and DMF (2 ml) were added with para-methoxybenzyl chloride (46 μL, 0.339 mmol), and the mixture was stirred overnight at 45° C. The resultant was added with water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and the resulting residues obtained after concentration under reduced pressure were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (21 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:26])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])[CH:10]=[CH:11][C:12]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=NN(C)C=1C1C=C(NC(=O)C2C=CC(OC)=CC=2F)C=CC=1O.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:91][C:92]([F:106])([F:105])[CH2:93][CH:94]([NH:97]C(=O)OC(C)(C)C)[CH2:95]O.[C:107]([OH:113])([C:109]([F:112])([F:111])[F:110])=[O:108]>C1COCC1>[F:110][C:109]([F:112])([F:111])[C:107]([OH:113])=[O:108].[NH2:97][CH:94]([CH2:93][C:92]([F:106])([F:105])[F:91])[CH2:95][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:26])[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)NC(CO)CC(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(OCC(N)CC(F)(F)F)c(-c3c(Cl)cnn3C)c2)c(F)c1
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (20.0 mg, 53.2 μmol) was dissolved in anhydrous THF (0.3 mL). Triphenylphosphine (15.4 mg, 58.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide/THF solution. The reaction was stirred for 5 minutes and then DIAD (16.6 μl, 85.2 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the reaction. The mixture was stirred at r.t. for 5 more minutes and then tert-butyl 4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (16.2 mg, 66.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added. The reaction was then stirred for 4 hours and checked by LC/MS. While the reaction had not gone to completion, pushing the reaction by heating or extending the reaction time did not seem to improve the yield. Thus, the solvent was evaporated, the resulting oil re-suspended in CH2Cl2 (0.5 mL) and TFA (20.5 μl, 266 μmol) was added (to remove the Boc-protecting group from the amine). The reaction was stirred overnight at room temperature. The next day, the solvent was removed and the resulting oil was re-dissolved in DMSO (1 mL). The product was purified by Prep LC/MS (0-50% B, 30 min) to yield N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate (8.1 mg, 13.0 μmol, 24.5%) as a colorless oil. LCMS m/z 501.3 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 2.48-2.86 (m, 2H), 3.75 (d, J=2.78 Hz, 3H), 3.87-3.97 (m, 1H), 3.89 (s, 3H), 4.10-4.43 (m, 2H), 6.85 (dd, J=12.88, 2.27 Hz, 1H), 6.91 (dd, J=8.72, 2.40 Hz, 1H), 7.30 (dd, J=9.09, 2.27 Hz, 1H), 7.61 (d, J=2.53 Hz, 1H), 7.65-7.69 (m, 1H), 7.76 (t, J=8.59 Hz, 1H), 7.90 (dd, J=8.97, 2.65 Hz, 1H).