Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[CH:9]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([C:25]4[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=4)[N:17]=[CH:16]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyridine (example E.30) (0.200 g, 0.51 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.122 g, 0.62 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 19%). MS (ISP) 362.3 [(M+H)+] and 364 [(M+2+H)+]; mp 230-233° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[NH2:39][NH2:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:39][NH2:40])=[O:18])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NN)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure E, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 82 mg, 0.176 mmol) in CH2Cl2 (8 ml) was added EDC (51 mg, 0.264 mmol) and DMAP (26 mg, 0.256 mmol), followed by hydrazine (7 mg, 0.264 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: O[CH:2]1[CH2:7][N:6]([C:8]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[CH:5]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:4][CH2:3]1.COCCN(S(F)(F)[F:46])CCOC>C(Cl)Cl>[F:46][CH:2]1[CH2:7][N:6]([C:8]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[CH:5]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:4][CH2:3]1
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(O)CCC2CNC(=O)c2cccc3cccnc23)s1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)c(C(=O)N2CC(F)CCC2CNC(=O)c2cccc3cccnc23)s1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of N-((5-hydroxy-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide (0.07 mmol, 0.036 g) in DCM (0.3 mL) was added to a mixture of bis(2-methoxyethyl)aminosulfur trifluoride (0.14 mmol, 0.027 mL) in DCM (0.2 mL) at −78° C. under argon. The resulting mixture was stirred at −78° C. for 1 h and at rt for another 1.5 h. The desired product was purified by preparative TLC to give N-((5-fluoro-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide with unidentified stereochemistry (Y: 16%). MS (ESI) 489 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([CH:21]([C:23]([OH:25])=[O:24])[CH3:22])(=[O:20])=[O:19])(=[O:9])=[O:8])[CH3:6])C.[OH-].[Na+].N>C(O)C>[C:23]([CH:21]([S:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:7]([CH:5]([CH3:6])[C:4]([OH:26])=[O:3])(=[O:9])=[O:8])(=[O:20])=[O:19])[CH3:22])([OH:25])=[O:24]
Reactant: CCOC(=O)C(C)S(=O)(=O)CCCCCCCCS(=O)(=O)C(C)C(=O)O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)S(=O)(=O)CCCCCCCCS(=O)(=O)C(C)C(=O)O

Procedure:
2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid was prepared according to general method as outline in example 1. Starting from 2[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid ethyl ester (3.0 g, 6.8 mmol), ethanol (15 mL) and 10 N sodium hydroxide (15 mL). Yield 2.7 g (98%); white solid mp 99-102° C.; MS 387 (M+NH3)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1.[O:20]1CCCC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:20][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: BrCc1ccc(Br)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(OCc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 4-bromobenzylbromide (1.26 g, 6.7 mmol) in tetrahydrofuran (10 mL) at 0° C. was added a sodium hydride (60% w/w dispersion in oil; 0.40 g, 10 mmol). The mixture was stirred for 1 hour at room temperature, then 2,5-dichloro pyridine (1 g, 6.7 mmol) was added in one portion and the reaction mixture was heated under reflux overnight. TLC The reaction mixture was cooled and partitioned between ethyl acetate (40 mL) and cold water (10 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude title compound (1.54 g, 76%). This was used without further purification.
Reaction SMILES: CO[C:3](=[NH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(=O)(O)[O-].[Na+].[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:26](OC)(=[O:31])[CH2:27][C:28]([CH3:30])=O>CO>[OH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[N:25]([CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:26](=[O:31])[CH:27]=[C:28]([CH3:30])[N:11]=1
Reactant: NCCc1ccccc1
Reactant: COC(=N)c1ccccc1O
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)n(CCc2ccccc2)c(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
2-Hydroxy-benzimidic acid methyl ester from step 1a (250 mg, 1.33 mmol) was dissolved in methanol (6 mL) which contained sodium bicarbonate (110 mg, 1.33 mmol). After stirring at room temperature for 30 min, phenylethylamine (165 □I, 1.33 mmol) was added. The mixture was stirred for 4 h at room temperature, and then methyl acetoacetate (1.5 mL) and xylenes (10 mL) were added. Methanol was removed by distillation using a Dean-Stark trap, and the reaction mixture was refluxed for 3 h. The solution was cooled to room temperature and added to dichloromethane (100 mL). The mixture was extracted with water (100 mL) and the organic layer was dried with sodium sulfate containing decolorizing carbon. After filtration and concentration on the rotary evaporator, toluene (10 mL) was added to the residue, and the mixture was placed in the freezer overnight. The precipitate was filtered off and washed with cold toluene (5 mL). The product was further purified by flash chromatography on silica gel (25 g) with ethyl acetate—hexanes (7:3) as an eluent yielding 2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one (120 mg, 22%) as a white solid.
Reaction SMILES: COC(=O)[CH:4]([N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C[Mg]Br.[C:33](C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C([O:47][CH2:48][CH3:49])C>O1CCCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:12]2[N:11]([CH:4]([CH:5]3[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[C:48]([CH3:49])([OH:47])[CH3:33])[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=2)=[CH:23][CH:24]=1
Reactant: CCOCC
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: COC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: C[Mg]Br
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To the solution of 3.0 g (7.16 mmol) (−)-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid methyl ester in 50 ml tetrahydrofuran were added dropwise 8.36 ml (25.1 mmol) methyl magnesiumbromide (3M in diethyl ether, commercially available) during 5 min. at room temperature. After 18 h the reaction mixture was poured onto 300 ml aqueous saturated potassium sodium tartrate solution and the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness. The red oil was taken up in tert-butyl methyl ether and stored in the fridge for 1 h. The precipitated solid was filtered off and washed with tert-butyl methyl ether to give a first batch of the desired compound as a slight red solid (49%). The mother liquor was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:tert-butyl methyl ether (100:0 to 50:50) to give a second batch of compound. Colorless solid (40%). MS (Turbo Spray): m/z=419.3 [M+H[ ].
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=O)[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1>C(O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=[N:2][OH:3])[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: NO
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C=NO)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.4 h

Procedure:
Hydroxylamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate (1.50 g, 19.4 mmol), and a mixture of ethanol-water (80:20, 15 mL) were stirred at room temperature for 0.4 hours. The aldehyde (Example 76, Step 3) (3.07 g, 9.0 mmol) was dissolved in a solution of ethanol-water (4:1, 25 mL) and added to this mixture and stirred at 100° C. for 1 hour. The reaction was filtered hot and the filtrate allowed to cool to room temperature. An orange solid crystallized in the filtrate which was collected by vacuum filtration. The solid was dissolved in ethyl acetate and the solution washed with water, brine, dried over MgSO4, concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-hexane yielding the oxime as a tan powder (1.50 g, 47%): mp 186.6–187.6° C. 1H NMR (acetone-d6/300 MHz) 10.87 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H, J=2.6 Hz), 7.60 (d, 1H, J=2.6 Hz), 6.02 (q, 1H, J=7.1 Hz), 4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=O)[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC[N:28]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:28])=[O:25])[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)c2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Br)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Yield: 88.2 %

Procedure:
A solution of 4-(7-bromo-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (100 mg), HOBt ammonium salt (227 mg) and EDCI hydrochloride (180 mg) in DMF (15 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (88 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:50]=[CH:51][C:52]=1[O:53][CH3:54])[CH2:32][O:33][C:34]([NH:36][C:37]1[N:45]=[CH:44][N:43]=[C:42]2[C:38]=1[N:39]=[CH:40][N:41]2[CH2:46][C:47](O)=[O:48])=[O:35]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:47](=[O:48])[CH2:46][N:41]2[CH:40]=[N:39][C:38]3[C:42]2=[N:43][CH:44]=[N:45][C:37]=3[NH:36][C:34]([O:33][CH2:32][C:31]2[CH:50]=[CH:51][C:52]([O:53][CH3:54])=[C:29]([O:28][CH3:27])[CH:30]=2)=[O:35])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1OC
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)cc1OC

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(3,4-dimethoxybenzyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.58 (s, 1H), 8.58 (s, 0.6H), 8.56 (s, 0.4H), 8.35 (m, 1H), 8.30 (s, 0.4H), 8.27 (s, 0.6H), 8.26 (m, 1H), 7.73 (m, 2H), 7.07 (s, 1H), 6.98 (d, 1H), 6.94 (d, 1H), 5.38 (s, 1.2H), 5.27 (s, 0.8H), 5.12 (s, 2H), 4.56 (s, 0.8H), 4.28 (m, 2.4H), 4.09 (t, 2H), 3.87 (t, 0.8H), 3.76 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:22]=[O:24])=[CH:8][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(N=C=O)cc1
Temperature: 75 °C
Yield: 159.1 %

Procedure:
To a mixture of (4-aminophenoxy)-acetic acid methyl ester 3 (15 g, 82.87 mmol) and triethylamine (16.77 g, 165.73 mmol) in toluene (225 ml) under nitrogen atmosphere at 0° C. was added triphosgene (9 g, 30.33 mmol) in one lot. The reaction was exo-thermic and the temperature rose to 25° C. Later the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temperature for 26 hours. The reaction mixture was cooled to room temperature, the solids were filtered off, and toluene was distilled off under vacuum to get crude 4, which was vacuum distilled to get pure 4 (10 grams, 58.3%) as a white powder with an m.p between 50-53° C.
Reaction SMILES: [CH3:1][C:2](C)=O.[F:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:17])[C:14]=2[F:16])[CH:9]=[CH:8][C:7]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].C(I)C>C1(C)C=CC=CC=1>[CH2:1]([O:18][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[C:14]([F:16])[C:13]([F:17])=[CH:12][CH:11]=2)[C:6]=1[F:5])[CH3:2]
Reactant: CC(C)=O
Reactant: Oc1ccc2ccc(F)c(F)c2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCI
Product: CCOc1ccc2ccc(F)c(F)c2c1F

Procedure:
An acetone (80 ml) solution of 1,7,8-trifluoro-2-naphthol (15 g), potassium carbonate (16 g), and ethyl iodide (26 g) was stirred for 10 hours at room temperature. Toluene (200 ml) was added in this reaction solution. The organic layer was removed, and the aqueous layer was extracted with toluene. The organic layers were combined, washed with brine, and concentrated. The residue was evaporated under reduced pressure, and 2-ethoxy-1,7,8-trifluoronaphthalene was obtained.
Reaction SMILES: [SH:1][C:2]1(CC(OCC)=O)[NH:6][NH:5][N:4]=[N:3]1.[NH3:13].[CH2:14]([OH:16])[CH3:15]>>[SH:1][C:2]1[N:3]([CH2:15][C:14]([NH2:13])=[O:16])[N:4]=[N:5][N:6]=1
Reactant: CCOC(=O)CC1(S)N=NNN1
Reactant: N
Reactant: CCO
Product: NC(=O)Cn1nnnc1S
Reaction time: 36 h

Procedure:
Ethyl 5-mercapto-1H-tetrazol-5-ylacetate (15.0 g) was dissolved in ethanol (50 ml), the solution was saturated with ammonia gas then set aside for 36 hours. The precipitated mass was collected, washed with ethanol (20 ml), dried and dissolved in water (100 ml). The solution was treated with decolourising charcoal, filtered, acidified with concentrated hydrochloric acid and cooled in an ice bath. The product crystallised as needles and was collected, washed with a little water and dried in vacuo, 9.51 g., (75.0%) m.p. 214°-216° C. (d), νmax (nujol) 1695 cm-1 ; δ[(CD3)2SO], 7.72 (2H,d, J=22 Hz, --NH2), 5.02 (2H,s, --CH2 --). Found: C, 22.39; H, 2.18; N, 43.82; S, 20.16. C3H5N5OS requires: C, 22.64; H, 3.17; N, 44.00; S, 20.14%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CN(C=O)C>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
To a solution of 4-fluoro-2-hydroxy-benzaldehyde (560 mg, 4 mmol) in DMF (10 ml) were added benzyl chloride (0.5 ml, 4.33 mmol), and K2CO3 (860 mg, 6.22 mmol). After heating at reflux for an hour, the reaction mixture was allowed to cool to room temperature and was poured into a mixture of EtOAc/H2O. The organic layer was separated, washed with H2O and dried over MgSO4. The resulting oil was purified by flash chromatography to give 2-benzyloxy-4-fluoro-benzaldehyde as pale oil (628 mg, 68%), 1H NMR (CDCl3, 300 MHz) δ: 5.17 (s, 2H), 6.74 (m, 2H), 7.36 (m, 5H), 7.88 (m, 1H), 10.51 (s, 1H).
Reaction SMILES: [N:1]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]=S.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH2:13].C(N(CC)CC)C.[NH:25]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:33]([O:32][C:30]([C:28]1[CH:29]=[N:25][N:26]([C:2](=[N:13][C:12]2[CH:11]=[C:10]([F:9])[CH:16]=[C:15]([F:17])[CH:14]=2)[NH:1][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:27]=1)=[O:31])[CH3:34]
Reactant: Nc1cc(F)cc(F)c1
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC(=Nc1cc(F)cc(F)c1)n1cc(C(=O)OCC)cn1
Reaction time: 3 h
Yield: 16.7 %

Procedure:
Ethyl isothiocyanatoformate (0.68 mL, 5.8 mmol) was added to a solution of 3,5-difluoroaniline (0.680 g, 5.27 mmol) and DCM (26 mL). After 3 h, triethylamine (2.20 mL, 15.8 mmol) was added to the reaction mixture, followed by ethyl pyrazole-4-carboxylate (0.812 g, 5.79 mmol), and EDCl (1.21 g, 6.32 mmol). After 1.5 h, the reaction mixture was diluted with DCM (25 mL), washed with water (3×30 mL) and with brine (50 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (3-45% EtOAc/hexanes) to yield the titled compound (0.323 g, 17% yield). MS (ESI/Cl): mass calcd. for C16H16F2N4O4, 366.1; m/z found, 367.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O)#[N:25].O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:29]([C:28]1[CH:27]=[C:26]([CH:34]=[CH:33][CH:32]=1)[C:24]#[N:25])[O:14]2
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 6.7 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (61 mg, 0.257 mmol) and K2CO3 (178 mg, 1.29 mmol) in acetone (3 mL) was added 3-cyanobenzoyl chloride (43 mg, 0.257 mmol). The reaction vessel was sealed and heated to 60° C. for 2 d. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 6 mg (7%) of 3-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile. Rf=0.33 (50% EtOAc/hexanes).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:32])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:34]1C=C[C:37](=[O:41])[N:38](C)[CH:39]=1.C([O-])([O-])=[O:43].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:32])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N:38]5[CH2:39][CH2:34][O:43][C:37]5=[O:41])[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(Br)ccc1=O
Reactant: CC1(C)OB(c2ccc3c(c2)CCN(CC(=O)N2CCN(C4CCC4)CC2)C3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CN1CCc2cc(N3CCOC3=O)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 100 °C

Procedure:
To a sealed tube charged with 2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1.00 g, 2.28 mmol), 5-bromo-1-methylpyridin-2(1H)-one (513 mg, 2.73 mmol, 1.2 eq.), Pd(PPh3)4 (100 mg, 0.087 mmol, 0.04 eq.) and K2CO3 (945 mg, 6.84 mmol, 3.0 eq.), are added dioxane (20 ml) and water (3 mL). The mixture is degassed with nitrogen for 5 min. The tube is sealed and heated at 100° C. overnight. The reaction mixture is cooled and partitioned between DCM (150 mL) and 1N NaOH (100 mL). The mixture is extracted with DCM (2×150 mL). The combined organic extracts are dried and evaporated to yield the crude product which is purified by silica gel column chromatography eluting with EtOAc/MeOH/NEt3 (95:5:3) to yield the title compound. 1H NMR (300 MHz, CDCl3) δ 7.61 (1H, dd), 7.47 (1H, d), 7.15 (1H, s), 7.06 (1H, d), 6.66 (1H, d), 3.72 (2H, s), 3.67-3.64 (m, 4H), 3.62 (3H, s), 3.37 (2H, s), 2.94 (2H, t), 2.81 (2H, t), 2.69 (1H, m), 2.32-2.27 (4H, m), 2.03-1.67 (6H); MS (+VE) m/z 421.49 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:21]=[C:20]3[C:15]([N:16]([CH3:23])[CH2:17][C:18](=[O:22])[NH:19]3)=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:21]=[C:20]3[C:15]([N:16]([CH3:23])[CH2:17][C:18](=[O:22])[N:19]3[CH2:28][C:27]#[CH:26])=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: C#CCBr
Reactant: CN1CC(=O)Nc2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CN(C)c2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.0 g of 7-(3-chloro-5-trifluoromethylpyridin-2yl)-1,2,3,4-tetrahydro-4-methylquinoxalin-2-one in 35 ml of dimethylformamide was added dropwise to a suspension of 0.2 g of 80% strength by weight sodium hydride in 35 ml of anhydrous dimethylformamide. After stirring for 15 minutes, 0.73 g of propargyl bromide was added to the reaction mixture. After 18 hours at 23° C., the reaction mixture was poured into 300 ml of ice water and extracted three times with 100 ml of tert-butyl methyl ether each time, after which the combined organic phases were washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated. Purification of the crude product was carried out by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate). Yield: 1.1 g (49%) of colorless crystals; m.p.: 128-129° C.