Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22]S(C)(=O)=O)[C:17]=2[N:27]=1.[ClH:28]>>[ClH:28].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[N:27]=[C:17]2[C:18](=[O:22])[NH:19][CH2:20][CH:21]=[C:16]2[N:15]=1
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2c(OS(C)(=O)=O)nccc2[nH]1
Agent: Cl
Product: COc1cc(OS(C)(=O)=O)ccc1C1=NC2=CCNC(=O)C2=N1
Temperature: 25 °C

Procedure:
0.65 g of 2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4-methanesulfonyloxy-imidazo[4,5-c]pyridine was dissolved in 35 ml of ethanolic hydrochloric acid, and the solution was stirred for an hour at room temperature. The precipitate which had formed was suction-filtered off and washed with ethanol.
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:17](Br)([Br:20])([F:19])[F:18]>C1COCC1>[Br:20][C:17]([F:19])([F:18])[C:9]#[C:8][CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:10])[CH3:11]
Reactant: FC(F)(Br)Br
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CC(F)(F)Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 759.1 %

Procedure:
To a solution of tert-butyl-dimethyl-prop-2-ynyloxy-silane (11.6 g, 6.78 mmol) in dry THF (190 mL) was added nBuLi (46.6 mL, 1.6 M solution in hexanes) dropwise (via an addition funnel) over 30 min at 0° C. under N2. The reaction mixture was stirred at rt for 1.5 h before being cooled to −78° C. Then, CF2Br2 (18.8 mL, 20.3 mmol) was added dropwise over 30 min. After stirring for 2.5 h at −78° C., the reaction mixture was quenched with a saturated solution of NH4Cl and was extracted with ether. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Vacuum distillation (0.35-0.7 Torr) provided (4-bromo-4,4-difluoro-but-2-ynyloxy)-tert-butyl-dimethyl-silane (15.4 g, 76% yield) as a yellow liquid (55-70° C.): 1H NMR (400 MHz, CDCl3) δ0.15 (s, 6H), 0.93 (s, 9H), 4.46 (t, J=4.08 Hz, 2H); 19F NMR (376.19 MHz, CDCl3) δ −33.01 (t, J=4.1 Hz, 2F).
Reaction SMILES: [C:1]1([N:11]=[C:12]=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl>C(O)C>[C:1]1([N:11]2[C:12]([SH:13])=[N:16][N:15]=[N:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: S=C=Nc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Sc1nnnn1-c1cccc2ccccc12
Temperature: 79 °C
Yield: 85 %

Procedure:
To a solution of 1-naphthalenylisothiocyanate (500 mg, 2.7 mmol) in ethanol (150 mL) was added sodium azide (2.8 g, 43 mmol) and the mixture was heated to 79° C. for 2 hours. The reaction mixture was then cooled to room temperature, aqueous HCl solution (12N, 1.5 mL) added and the mixture concentrated. The resulting residue was diluted with ethyl acetate and extracted with aqueous NaOH solution (1N) and the aqueous layer acidified with aqueous HCl solution (12N) until a precipitate formed. The precipitate was collected and used in the next step without further purification (520 mg, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:6][CH:7]=1.[C-:25]#[N:26].[K+]>CS(C)=O>[C:25]([C@@H:11]1[CH2:10][N:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1)#[N:26]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1c1cccc(F)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@@H]1c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (I-29) (165 mg, 0.46 mmol), potassium cyanide (36 mg, 0.55 mmol) and DMSO (2 mL) was heated at 90° C. for 3 hours. After cooling, the reaction mixture was partitioned in Et2O and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography, eluted with EtOAc/Hex (0-50% gradient) to yield (2R,4S)-tert-butyl 4-cyano-2-(3-fluorophenyl)-pyrrolidine-1-carboxylate (I-30) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 1 H), 7.02-6.93 (m, 2 H), 6.87 (d, J=9.6 Hz, 1 H), 5.16r1 (bs, 0.4 H), 5.00r2 (bs, 0.6 H), 4.00-3.73 (m, 2 H), 3.16 (bs, 1 H), 2.67 (bs, 1 H), 2.25-2.21 (m, 1 H), 1.49 (bs, 3 H), 1.23 (bs, 6 H). MS m/z 313.1 (M+23)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)#[CH:21].C(N(CC)CC)C>CN(C=O)C.[Cu](I)I.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]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:21]#[C:20][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)=[C:9]([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)CSCc1nc2ccc(Cl)cn2c1I
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CSCc1nc2ccc(Cl)cn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
In an argon atmosphere, 27 g (59.8 mmol) of ethyl 2-((6-chloro-3-iodoimidazo[1,2-a]-pyridin-2-yl)methylthio)acetate, 9.51 ml (65.8 mmol) of 1-ethynyl-3-(trifluoromethyl)benzene, 1.139 g (5.98 mmol) of copper iodide and 125 ml (897 mmol) of triethylamine are loaded in 100 ml of DMF. Argon was bubbled in the solution for 10 min, and then 2.74 g (2.99 mmol) of Pd2(dba)3 were added. The mixture was stirred for 1 h at r.t. The catalyst was filtered on folded paper, the solution was poured onto 300 ml of water, extracted with 2×200 ml of ethyl acetate, the collected organic phases were washed with 3×150 ml of water and once with 150 ml of brine, dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The residue was purified on a silica cake, and eluted with a heptane/ethyl acetate mixture. 23.21 g (yield=85%) of ethyl 2-((6-chloro-3-((3-(trifluoromethyl)phenyl)ethynyl)-imidazo[1,2-a]pyridin-2-yl)methylthio)acetate were obtained as a yellow solid. LC-MS: m/z=453 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.91 (dd, J=1.9, 0.6 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.71 (ddd, J=14.3, 9.4, 4.3 Hz, 3H), 7.47 (dd, J=9.5, 2.0 Hz, 1H), 4.18-3.93 (m, 4H), 3.46 (s, 2H), 1.11 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([Br:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].C([O-])=O.[NH4+].O.[CH:20]([NH2:22])=O>>[Br:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:20][NH:22][C:4]2=[O:5]
Reactant: NC=O
Reactant: COC(=O)c1cc(Br)c(OC)cc1N
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of methyl 2-amino-5-bromo-4-methoxybenzoate (75 mg, 0.29 mmol) and ammonium formate (38 mg, 0.8 mmol) in formamide (1 mL) was heated at 165° C. for 18 h. The mixture was allowed to cool to room temperature then diluted with an excess of water. The solid formed was collected by filtration and washed with water then ethyl acetate and dried to give 6-bromo-7-methoxyquinazolin-4(3H)-one (53 mg, 72% yield) as a pale yellow solid. MS (EI) for C9H7BrN2O2: 255, 257 (MH+).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[NH:37]N>>[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=468.2 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.P(Br)(Br)[Br:14].CCOCC>C(Cl)Cl>[Br:14][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: BrP(Br)Br
Reactant: SCCc1c[nH]c2ccccc12
Solvent: CCOCC
Solvent: ClCCl
Product: BrCCc1c[nH]c2ccccc12

Procedure:
The starting materials of formula II in which X1 is mercapto, --S--SO3Na or --S--SO3K, and R2, R3, R4, R5, R6 and R7 are as defined in the first instance are obtained by the following process: The appropriate compound of formula II (XI =OH) described above, is treated with phosphorus tribromide in an inert solvent, for example, ether or methylene chloride- to afford the corresponding 3-(2-bromoethyl)-indole derivative. The latter compound is then converted to the desired starting material of formula II (X1 = SH) by a procedure similar to that described by N. N. Suvorov and V. N. Buyonav, Khim.-Farm. Zh., 1, (1967), [Chem. Abstr. 67, 7347a (1967)], for converting 3-(2-bromoethyl)-indole to indole 3-ethanethiol (II; R2, R3, R4, R5 and R6 = H and X1 = SH). Accordingly, the appropriate 3-(2-bromoethyl)-indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium β-(3-indolyl)ethyl thiosulfate derivative, respectively: namely the desired starting materials of formula II (X=--S--SO3Na or --S--SO3K). Treatment of the latter product with strong alkali, for example, sodium or potassium hydroxide, yeilds the corresponding bis[ω-(3-indolyl)ethyl]-disulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II (X1 = SH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[CH:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.27) (0.286 g, 0.75 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.234 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.343 g, 97%). MS (ISP) 461.3 [(M+H)+]; mp 194-196° C.
Reaction SMILES: [CH:1]12[CH2:6][CH:4]([CH2:5]1)[CH2:3][N:2]2[C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:16]([NH2:19])=[N:17][CH:18]=2)[CH:10]=[C:9]([N:24]2[CH2:29][C@@H:28]3[CH2:30][C@H:25]2[CH2:26][NH:27]3)[N:8]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(C(C)C)C(C)C)C>CS(C)=O>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:11]2[N:12]=[C:7]([N:2]3[CH2:3][CH:4]4[CH2:5][CH:1]3[CH2:6]4)[N:8]=[C:9]([N:24]3[CH2:29][C@@H:28]4[CH2:30][C@H:25]3[CH2:26][N:27]4[C:31](=[O:33])[CH3:32])[CH:10]=2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CN4)nc(N3CC4CC3C4)n2)cc1C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(N2CC3CC2C3)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 45.8 %

Procedure:
To a solution of 5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (80 mg, 0.22 mmol) in DMSO (2 mL) was added acetic anhydride (46 mg, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL). The mixture was stirred at room temperature for 25 min. The mixture was concentrated in vacuum and the residue was purified by Prep-HPLC (BASE) to provide 1-((1S,4S)-5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone (46.34 mg, 40.0% yield). LCMS (ESI): [MH]+=459.9; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.36 (s, 1H), 6.79 (s, 2H), 6.53-6.21 (m, 1H), 5.10-4.89 (m, 1H), 4.80-4.78 (m, 1H), 4.74-4.63 (m, 1H), 3.55-3.51 (m, 1H), 3.44-3.35 (m, 2H), 3.23-2.84 (m, 4H), 2.82 (s, 1H), 2.00 (s, 1H), 1.91 (s, 3H), 1.83-1.81 (m, 2H), 1.29 (d, J=2.0 Hz, 2H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[Na].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].Cl>[Na].C1COCC1>[C:20]([O:19][C:15](=[O:18])[CH2:16][CH2:17][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([CH3:23])([CH3:22])[CH3:21]
Reactant: OCCOCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCO
Yield: 72.5 %

Procedure:
To 300 mL of anhydrous THF was added 80 mg (0.0025 mol) of sodium metal and 128 mL of tetraethylene glycol 4a (0.94 mol) with stirring (Seitz and Kunz, J. Org. Chem., 62:813-826 (1997)). After the sodium had completely dissolved, tert-butyl acrylate (24 mL, 0.33 mol) was added. The solution was stirred for 20 hrs at room temperature and neutralized with 8 mL of 1.0 M HCl. The solvent was removed in vacuo and the residue was suspended in brine (250 mL) and extracted with ethyl acetate (3×125 mL). The combined organic layers were washed with brine (100 mL) then water (100 mL), dried over sodium sulfate, and the solvent was removed. The resulting colorless oil was dried under vacuum to give 77.13 g (73% yield) of product 9a (FIG. 7). 1H NMR: 1.40 (s, 9H), 2.49 (t, 2H, J=6.4 Hz), 3.59-3.73 (m, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH:34]1[CH2:38][NH:37][CH:36]([CH2:39][OH:40])[CH2:35]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH:34]5[CH2:35][CH:36]([CH2:39][OH:40])[NH:37][CH2:38]5)[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CNC1CNC(CO)C1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CNC(CO)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-hydroxymethyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and (4-Methylamino-pyrrolidin-2-yl)-methanol following General Procedure C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:14]=[CH:15][C:16](O)=[O:17].OS(O)(=O)=O>C1COCC1>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:16](=[O:17])[CH2:15][CH:14]([C:13]3[CH:19]=[CH:20][C:21]([OH:22])=[C:11]([O:10][CH3:9])[CH:12]=3)[O:5]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: COc1cc(C=CC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(C2CC(=O)c3ccc(O)cc3O2)ccc1O
Yield: 90 %

Procedure:
Resorcinol (15), 3-methoxy-4-hydroxy-cinnamic acid (16) and H2SO4 (5%) were refluxed in THF for 4 hours to provide 7,4′-dihydroxy-3′-methoxy flavanone (17) (90% yield). The product, 7,4′-dihydroxy-3′-methoxy flavanone (17) was then treated with 10% sodium hydroxide at 80° C. for 1 hour, followed by reduction with sodium borohydride in propanol to provide, as confirmed LC-MS/PDA detection, 1-(2,4-dihydroxyphenyl)-3-(3′-methoxy-4′-hydroxyphenyl)-1-propanol (19). The crude product exhibits quite strong tyrosinase inhibitory activity. The mixture was further purified by HTP.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:10]1[N:9]2[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:8]2[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:12][CH:11]=1
Reactant: CCOC(=O)c1cn2ccnc(N3CCOCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound 1c (3.2 g, 9.0 mmol) in DCM (100 mL) at 0° C. was added NBS (1.6 g, 9.0 mmol) portionwise. The reaction mixture was allowed to stir at rt for 10 min, and subsequently was washed with a saturated aqueous sodium bicarbonate (2×100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to give compound 21a as an off-white solid. Mass Spectrum (LCMS, ESI pos.) Calcd. For C13H15BrN4O3: 356.2 (M+H). Found 356.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH2:38]([S:40][CH2:41][CH2:42][NH2:43])[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:43][CH2:42][CH2:41][S:40][CH2:38][CH3:39])=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CCSCCN
Agent: Cl
Product: CCSCCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-(ethylthio)ethylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[C:24]1(=O)[O:29][C:27](=[O:28])[CH2:26][CH2:25]1>CN(C=O)C>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([N:1]5[C:27](=[O:28])[CH2:26][CH2:25][C:24]5=[O:29])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(N3CCOc4ccc(N5C(=O)CCC5=O)cc43)sc2C(=O)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A mixture of Example 42 (50 mg, 0.15 mmol) and succinic anhydride (20 mg, 0.15 mmol) in DMF (4 mL) was stirred at 140° C. under microwave irradiation for 1 h. The reaction mixture was concentrated in vacuo, dissolved in acetic acid and stirred at 140° C. under microwave irradiation for 1 h. It was concentrated in vacuo and purified by preparative HPLC (Method 7) to give the title compound (21 mg, 34%) as an off-white solid. δH (CDCl3) 8.05 (1H, d, J 2.1 Hz), 7.11-6.91 (2H, m), 5.45 (1H, s), 4.41-4.32 (2H, m), 4.19-4.10 (2H, m), 2.92 (4H, s), 2.88 (2H, s), 1.39 (6H, s). LCMS (ES+) 413.0 (M+H)+, RT 2.58 minutes (Method 2).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([N:17]=[C:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[CH2:10]([N:17]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][C:19]2[CH2:20][CH2:21][CH2:22][C:18]1=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CN=C2CCCC2)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc2c(n1Cc1ccccc1)CCC2
Reaction time: 2 h

Procedure:
Add dropwise 3.9 gm of ethyl bromopyruvate in 50 ml of ethanol to a flask containing 3.46 gm of benzyliminocyclopentane and 2.0 g of triethylamine in 50 ml of ethanol at 0° C., stir for 2 hours, then heat to reflux for 2 hours. Concentrate the reaction mixture and partition between 1N HCl and ether. Dry the ether extract over magnesium sulfate, filter, ooncentrate under high vacuum to obtain a brown oil and distill in a kugelrohr at 190°-210°/0.1 mm to obtain the title compound of Part A as a yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:12][CH:11]([CH3:13])[CH2:10][C:9]=2[CH:14]=1)(=O)=O.C(O)(=O)C.[Sn].Cl>O>[SH:2][C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:12][CH:11]([CH3:13])[CH2:10][C:9]=2[CH:14]=1
Reactant: CC1Cc2cc(S(=O)(=O)Cl)cc(C(=O)O)c2O1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2cc(S)cc(C(=O)O)c2O1

Procedure:
216 g of 5-chlorosulphonyl-2-methyl-2,3,-dihydrobenzofuran-7-carboxylic acid, 585 ml of acetic acid and 348 g of tin were introduced into a 6-liter round-bottomed flask and 1560 ml of concentrated hydrochloric acid (d =1.18) were then added dropwise, while maintaining the temperature between 45° and 55° C. The contents were then heated for 2 hours at 55°-60° C. until the tin was completely dissolved, and the solution which was poured into 12 liters of water was then filtered. The crystals formed were drained, washed with water and dried at 40° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[O:20][CH2:19][CH2:18][CH2:17]1.Cl>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]2[CH2:16][CH2:17][CH2:18][C:19]2=[O:20])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCO1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: O=C1CCCN1c1ccc(OCc2ccccc2)cc1
Yield: 30.8 %

Procedure:
20.3 g (101.9 mmol) 4-benzyloxyaniline and 9.1 ml (119.2 mmol) gamma-butyro-lactone are treated with 3 ml concentrated hydrochloric acid. The mixture is heated 20 hours to 160° C., then 5.5 hours to 200° C. After cooling, the mixture is extracted with 250 ml ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and dried. Evaporation of the solvent and recrystallisation from diethyl ether yields 8.4 g (31%) of a brownish solid. MS: m/e=267 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)#[CH:2].I[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[C:14]([OH:16])=[O:15]>>[F:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=2[O:20][CH3:21])[C:14]([OH:16])=[O:15])[CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1cccc(F)c1
Reactant: COc1cc(C(=O)O)cc(I)c1OC
Product: COc1cc(C(=O)O)cc(C#Cc2cccc(F)c2)c1OC

Procedure:
3-(3-Fluorophenylethynyl)-4,5-dimethoxybenzoic acid was prepared by coupling 1-ethynyl-3-fluorobenzene with 3-iodo-4,5-dimethoxybenzoic acid Method R. The crude product was purified via flash column chromatography on silica gel (5% MeOH in CH2Cl2 as an eluent) to give 3-(3-fluorophenylethynyl)-4,5-dimethoxybenzoic acid in 95% yield. ESMS: m/z 299.3 [M−H].
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=1)(=[O:4])[CH2:2]C.CO.C[N:16]([CH3:19])C=O>>[N:16]1[C:19]2[CH:11]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][C:2]=1[C:1]([NH:5][C:6]1[CH:12]=[CH:11][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CCC(=O)Nc1ccc(N)cc1
Reactant: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccccc1)c1nc2ccccc2[nH]1

Procedure:
14.4 g (0.05 mol) of dibenzimidazo(1,2a,1',2'-d)tetrahydropyrazine-6,13-dione and 30 g (0.18 mol) of 4-propionylaminoaniline are heated under reflux in 70 ml of dry dimethylformamide for 3 hours. After cooling down, about 700 ml of methanol are added. The precipitated solid is filtered off with suction and washed with methanol and dried to leave 20.7 g of the benzimidazole-2-carboxanilide of the formula ##STR93## Melting point 289°-291° C.