Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:33][CH:34]=3)[O:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1COCCn1ccnn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 201 mg (0.847 mmol) 3-Fluoro-4-(2-[1,2,3]triazol-1-yl-ethoxylmethyl)-phenol in 5 ml dimethylformamide was treated with 22.5 mg ( 0.890 mmol) 95% sodium hydride and stirred at room temperature for 20 min, then 257 mg (0.847 mmol) 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued for 14 h. After addition of water, the precipitate was isolated, washed thoroughly with water, twice with ether and dried to give 1-[2-(2-fluoro-4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzyloxy)-ethyl]-1H-[1,2,3]triazole.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13].C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12](=[O:13])[C:11]([F:18])([F:17])[F:10]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NCc1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 2-bromobenzylamine (1.3 mL, 10.8 mmol) in methanol (5 mL) was added ethyl trifluoroacetate (1.54 mL, 21.6 mmol) and triethylamine (1.4 mL, 10.8 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated under vacuum to yield N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (3.15 g, quant.). HPLC ret. time 2.86 min, 10-99% CH3CN, 5 min run; ESI-MS 283.9 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:2]2[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
an oven dried flask was added 4-bromo-naphthalene-1-carboxylic acid In (1.36 g, 0.0054 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL) and aluminum trichloride (0.676 g, 0.0051 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(-n2cnnn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nc(-n2cnnn2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 2 ml of ethanol was dissolved 0.172 g of 3-amino-4,5-diethoxycarbonyl-2-phenyl-6-(tetrazol-1-yl)pyridine, whereto 1 ml of hydrazine monohydrate was added. The mixture was reacted at 90° C. for 2 hours. After 15 ml of ethanol was added, the mixture was cooled. The precipitate was collected by filtration and washed with ethanol. The thus-obtained precipitate was dissolved in 20 ml of hot water, and 0.7 ml of acetic acid was added. The mixture was cooled, and the resulting precipitate was collected by filtration, washed and dried, to give 0.11 g of the title compound as yellow crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[S:23]1[C:27](C(Cl)=O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2>>[S:23]1[C:27]([C:3](=[O:2])[CH2:4][C:5]2[N:9]3[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]3=[N:7][C:6]=2[C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: O=C(Cl)c1cc2ccccc2s1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cc3ccccc3s2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid methyl ester 35a and benzo[b]thiophene-2-carbonyl chloride using the procedure of Method C described above. 1H NMR (400 MHz, CDCl3) 2.31 (s, 3H), 2.42 (s, 3H), 4.68 (s, 2H), 7.04 (d, J=9.1 Hz, 1H), 7.29 (d, J=7.7 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.44 (5.8 Hz, 1H), 7.56 (m, 3H), 7.70 (m, 2H), 7.83 (m, 2H). Mass spectrum (m/e) 397 (M+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:12][CH2:11][N:10]([C:13](=[O:24])[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)(=O)=O.[C:33]1([N:39]2[C:43]3([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:42](=[O:49])[NH:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:32][C:27]1[CH:26]=[C:25]([C:8]2([CH2:7][CH2:6][N:46]3[CH2:45][CH2:44][C:43]4([N:39]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:40][NH:41][C:42]4=[O:49])[CH2:48][CH2:47]3)[CH2:12][CH2:11][N:10]([C:13](=[O:24])[C:14]3[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:9]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: COc1cccc(OC)c1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)N1CCC(CCN2CCC3(CC2)C(=O)NCN3c2ccccc2)(c2ccc(Cl)c(Cl)c2)C1
Yield: 51.2 %

Procedure:
2-[1-(2,6-Dimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl methanesulfonate (200 mg, 0.398 mmol), and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (100 mg, 0.432 mmol) were dissolved in THF/H2O (4 mL /1 mL) and treated with potassium carbonate (110 mg, 0.796 mmol, 2 eq.) at reflux for 22 hours. The solution was concentrated in vacuo and the aqueous phase was extracted (3×) with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (40 g) with a gradient from ethyl acetate to 10% methanol in dichloromethane to give 130 mg (51%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>CN(C=O)C.O>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:23]=[CH:22][C:21]4[C:17](=[CH:18][N:19]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[N:20]=4)[CH:16]=3)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(=O)CCl
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3nn(CC(=O)N(C)C)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), potassium iodide (1 mg) and 2-chloro-N,N-dimethylacetamide (140 mg; 1.15 mmol). After stirring at RT for 72 hours the mixture was poured in water (20 ml) and stirred at RT for 1 hour. The solid was removed by filtration, washed with water and dried. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid, together with 6-[(cyclopropylmethyl)(propyl)amino]-N-{1-[2-(dimethylamino)-2-oxoethyl]-1H-indazol-5-yl}pyrimidine-4-carboxamide (Example 115 below).
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]1([CH3:37])[CH2:36][CH2:35]1)[CH:29]=O.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]1([CH3:37])[CH2:36][CH2:35]1)[CH2:29][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=1
Reactant: CC1(c2ccc(C=O)cc2Cl)CC1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2Cl)CC1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 3-chloro-4-(1-methylcyclopropyl)-benzaldehyde (86 mg, 0.44 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (84 mg, 0.44 mmol) and sodium borohydride (25 mg, 0.66 mmol). The desired product (145 mg, 89%) was isolated without further purification as a colorless oil. MS (ISP) 368.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:34])=[C:30]([CH2:32]O)[N:31]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:34])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CO
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(Cl)cc3)oc2C)c2ccoc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 21 f], [rac]-2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (example 120 e]) was reacted with [2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanol (R. C. Self, W. E. Barber, J. P. Machin, J. M. Osbond, C. E. Smithen, B. P. Tong, J. C. Wickens, D. P. Bloxham, D. Bradshaw, C. H. Cashin, B. B. Dodge, E. J. Lewis, D. Westmacott, J. Med. Chem. 1991, 34, 772-777) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Yield: 99.9 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 69d) (308 mg, 0.62 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added butyrylchloride (90 μL, 0.87 mmol) at room temperature. The resultant solution stirred for 90 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (35 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (352 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.42 (s 1H), 7.93 (dm, J=8.8 Hz, 2H), 7.85 (dm, J=8.8 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 5.74 (d, J=9.2 Hz, 1H), 5.03 (dd, J=6.5, 9.0 Hz, 1H), 4.66 (pentet, J=6.3 Hz, 1H), 2.38 (t, J=7.2 Hz, 2H), 2.35 (s, 3H), 1.70 (sextet, J=7.4 Hz, 2H), 1.44 (d, J=6.1 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H), 0.81 (s, 9H), 0.09 (s, 3H), −0.01 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:11])[C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)nc1
Reaction time: 8 h

Procedure:
To a solution of the tert-butyl 4-(5-(((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 46-2 in DCM (3.0 mL) was added trifluoroacetic acid (1.0 mL) and the solution was stirred overnight. The reaction mixture was concentrated, redistributed between ethyl acetate and 5% Na2CO3 solution and the organic phase dried over Na2SO4. Concentration with rotavap gave crude N-((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-6-(piperazin-1-yl)nicotinamide 46-3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)nc1
Temperature: 120 °C
Yield: 83.6 %

Procedure:
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (233 mg, 0.958 mmol), methyl 6-chloronicotinate (164 mg, 0.988 mmol) and potassium carbonate (265 mg, 1.92 mmol) in DMF (5.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (303 mg, 79%) as a white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2](CCO)=[CH:3][CH:4]=[CH:5][CH:6]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:27]=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:10]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=[CH:12][CH:13]=[CH:14][CH2:15]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCc1ccccc1-c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OCCC2(c3ccccc3)C=CC=CC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
2-biphenyl ethanol (1 g, 5 mmol), 4-nitrophenol (834 mg, 6 mmol), and triphenylphosphine (1.59 g, 6 mmol) was dissolved in 20 mL dichloromethane. The solution was chilled in an ice-water bath prior to the addition of diethylazodicarboxylate (949 μl, 6 mmol). The reaction was then stirred overnight, and the ice-water bath slowly warmed to room temperature. Crude product was purified by flash chromatography to yield 640 mg crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.1 (d), 7.6 (m), 7.47–7.41 (m), 7.34 (m), 7.17 (m), 4.39 (t, 2H), 3.13 (t, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Li]>O1CCCC1>[C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][C:15]1[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:29])[CH3:2])=[CH:9][CH:8]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:28]
Reactant: CC(=O)c1ccc(CC(=O)Nc2cccnc2Oc2cccc(C#N)c2)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CC(=O)Nc2cccnc2Oc2cccc(C#N)c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a solution of 2-(4-Acetyl-phenyl)-N-[2-(3-cyano-phenoxy)-pyridin-3-yl]-acetamide (0.360 grams, 0.96 mmole) in tetrahydrofuran (15 ml) at −78° C. 1.0 M methyl lithium (2.03 ml, 2.03 mmole) in tetrahydrofuran (20 ml) was added and stirred at −78° C. for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give a white solid which was purified by chromatography on silica eluting with 40% ethyl acetate/hexane. Recrystalization from ethyl acetate/hexane gave white crystals (0.115 g). M.P. 97-99° C.; Anal. calcd. for C23H21N3O3: C, 71.30; H, 5.46; N, 10.85. Found: C, 70.96; H, 5.30; N, 10.69.
Reaction SMILES: O[CH:2]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:24]1[CH:28]=[C:27]([CH3:29])[S:26][CH:25]=1)[C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.C(O)(=O)C>CO.C(OCC)(=O)C>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH2:2][C:3]3[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=3)=[C:14]([C:24]3[CH:28]=[C:27]([CH3:29])[S:26][CH:25]=3)[NH:15]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(C(O)c2c(-c3csc(C)c3)[nH]c3cc(OC)ccc23)n1
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cc2c(-c3csc(C)c3)[nH]c3cc(OC)ccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of methyl 6-{hydroxy-[6-methoxy-2-(5-methylthiophen-3-yl)-1H-indol-3-yl]methyl}pyridine-2-carboxylate (335 mg) and a boran-2-picoline complex (92.1 mg) in methanol (1.7 mL) was added acetic acid (1.7 mL), and this mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (255 mg). 1H-NMR (CDCl3) δ ppm: 2.48-2.53 (3H, m), 3.85 (3H, s), 4.05 (3H, s), 4.54 (2H, s), 6.74 (1H, dd, J=2.2, 8.6 Hz), 6.88 (1H, d, J=2.2 Hz), 6.96-7.01 (1H, m), 7.17-7.22 (2H, m), 7.29 (1H, d, J=8.6 Hz), 7.62 (1H, t, J=7.8 Hz), 7.93-7.98 (1H, m), 8.01 (1H, br s).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([O:12][CH3:13])(=[O:11])[CH2:6][CH2:7][C:8]([CH3:10])=O.II.[CH3:16]O>C(O)C.C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:10]=[C:8]([CH2:7][CH2:6][C:5]([O:12][CH2:13][CH3:16])=[O:11])[N:4]=1
Reactant: CO
Reactant: NC(N)=S
Reactant: COC(=O)CCC(C)=O
Agent: II
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCc1csc(N)n1
Reaction time: 6 h
Yield: 11 %

Procedure:
Thiourea (4.86 g, 64 mmol) was dissolved in ethanol (60 mL) at 60° C. Methyl levulinate (4.16 g, 32 mmol) and iodine (8.11 g, 32 mmol) were added and the temperature was elevated to reflux. The mixture was stirred for 6 h and the solvent was evaporated. Ethyl acetate, water and sodium bicarbonate solution was added and mixture was extracted. The organic phase was dried (sodium sulphate), filtered and the solvent was evaporated giving 6 g crude product. The crude was flash cromatographed on SiO2 eluting with 5% methanol in DCM giving ethyl 3-(2-amino-1,3-thiazol-4-yl)propanoate (1.33 g, 7.14 mmol, 11%). This material (1.23 g, 6.14 mmol) was sulphonylated with 3-chloro-2-methylbenzenesulphonyl chloride (1.79 g, 7.98 mmol) in pyridine (5 mL) according to METHOD A giving 1.91 g (80%) of the title product: MS (Ionspray, [M+H]+) m/z 388. Anal. Calcd. (found) for C15H17ClN2O4S2: C, 46.3 (46.3)%; H, 4.4 (4.5)%; N, 7.2 (7.0)%.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]([CH2:12][CH:13]1[O:18][CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14]1)C)C1C=CC=CC=1.C(O)C>[C].[Pd].O>[OH2:18].[ClH:1].[ClH:1].[CH3:3][NH:10][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CN(Cc1ccccc1)CC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCC1CNCCO1

Procedure:
A mixture of 58 g of 2-chloromethyl-4-benzylmorpholine, 62.3 g of N-benzyl-N-methylamine and 38.6 g of sodium iodide in 220 ml of dimethylformamide is refluxed under stirring at 140° C. for 6 hours. After completion of the reaction, the dimethylformamide is distilled off under reduced pressure, water is added to the residue and the mixture is subjected to extraction with ethyl acetate. After washing with water, the resultant mixture is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is treated in 37% hydrochloric acid-ethanol to give 2-(N-benzyl-N-methylaminomethyl)-4-benzylmorpholine dihydrochloride as white crystals. The obtained hydrochloride compound (29.7 g) is subjected to catalytic reduction with 50 ml of ethanol, 80 ml of water and 3 g of 10% palladium-carbon. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the solvent of the filtrate is distilled off to give 2-(methylaminomethyl)morpholine dihydrochloride monohydrate as white crystals, melting at 122°-124° C.