Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Cl.N1C=CC=CC=1>CC(O)=O>[C:5]1([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(/C=C/c2cc(OC)cc(OC)c2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Temperature: 90 °C

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stir bar was added 8 (2.7 g, 10 mmol) and pyridine hydrochloride (10.4 g, 90 mmol, 9 equiv). A reflux condenser was equipped and the reaction mixture was refluxed for 2 h under an N2 atmosphere. Afterwards, the mixture was allowed to cool to ˜90° C. and quenched into H2O (200 mL) whereupon a purplish colored solid precipitated. The mixture was extracted with EtOAc (50 mL×3). The extracts were collected and diluted with hexanes (100 mL) and then filtered through a thin pad of silica gel to remove dark colored, polar impurities. The filtrate was evaporated in vacuo leaving an off-white solid. The crude product was slurried with HOAc and filtered to give resveratrol as a tan microcrystalline powder (450 mg, 20%), mp. 258-261° C., lit. 261° C. 1H NMR (DMSO): δ 9.59 (s, OH), 9.23 (s, 20H), 7.41 (d, J=8.9 Hz, 2H), 6.95 (d, Jab=16.3 Hz, 1H), 6.82 (d, Jab=16.3 Hz, 1H), 6.76 (d, J=8.9 Hz, 2H), 6.39 (d, J=2.0 Hz, 2H), 6.13 (t, J=2.1 Hz, 1H); 13C NMR (DMSO): δ 158.58, 157.28, 139.36, 128.15, 127.96, 127.92, 125.74, 115.61, 104.41, 101.87. Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.40; H, 5.44.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1([CH3:18])[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:9]2[S:10][CH:11]=[CH:12][C:8]1=2.[C:19]([O-])([O-])=[O:20].[K+].[K+].C(Cl)Cl>C(Cl)Cl.CN(C=O)C>[CH3:6][C:7]1([CH3:18])[C:8]2[CH:12]=[C:11]([CH:19]=[O:20])[S:10][C:9]=2[C:13]2[S:14][CH:15]=[CH:16][C:17]1=2
Reactant: CC1(C)c2ccsc2-c2sccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)c2ccsc2-c2sc(C=O)cc21
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
1 mL POCl3 was added to a vigorously stirred solution of 4,4-dimethyl-4H-cyclopenta[2,1-b:3,4-b′]dithiophene (381.2 mg, 1.85 mmol) in 6 mL 5:1 CH2Cl2/DMF solvent mixture. The mixture was sealed in a pressure vessel and stirred at 100° C. for 10 min. The solution turned yellow then red upon cooling down. The reaction mixture was then basified with K2CO3 solution, stirred for 30 min more at room temperature to allow complete hydrolysis. The organic product was then extracted with CH2Cl2, concentrated, and purified by column chromatography (SiO2, CH2Cl2) to furnish a yellow oil that solidifies on standing (204 mg, 47%). Rf (silica gel, CH2Cl2)=0.41; 1H NMR (400 MHz, CDCl3): δ 1.50 (s, 6 H, 2 CH3), 7.05 (d, J=4.8 Hz, 1 H, ArH), 7.40 (d, J=4.8 Hz, 1 H, ArH), 7.63 (s, 1 H, ArH), 9.83 (s, 1 H, CHO); MS (EI): m/z=234 [M]+.
Reaction SMILES: [C:1]([CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2].[H][H]>C(O)C.[Pd].C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: Cn1c(-c2cccnc2)c(CCCCCC=CC(=O)O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1c(-c2cccnc2)c(CCCCCCCC(=O)O)c2ccccc21

Procedure:
3-(7-Carboxyhept-6-enyl)-2-(3-pyridyl)-1-methylindole (100 mg) is dissolved in 10 ml of absolute ethanol with a catalytic amount of 10% palladium of charcoal and hydrogenated at 1 atmosphere pressure. After 1 mole of hydrogen is consumed, the catalyst is removed by filtration and washed with a few milliliters of ethanol. The combined filtrates are concentrated in vacuo to yield 3-(7-carboxyheptyl)-1-methyl-2-(3-pyridyl)indole.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]2[C:3]=1[C:4]1[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=1[NH:6]2.[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29]([C:31]2[CH:36]=[C:35]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]4[C:3]=3[C:4]3[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=3[NH:6]4)[CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:26][CH2:27]1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(Cl)c3c2c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(-c4cccc(C(=O)NC5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropylcarbamoyl)phenyl boronic acid using an analogous procedure to that described in the preparation of compound 83. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (dd, J=3.92, 2.40 Hz, 2H) 0.71 (dd, J=6.95, 2.40 Hz, 2H) 1.23 (s, 1H) 2.26 (s, 3H) 2.65 (s, 3H) 2.87 (d, J=5.05 Hz, 6H) 3.29 (q, J=5.98 Hz, 2H) 3.61 (q, J=6.15 Hz, 2H) 7.20 (s, 1H) 7.50 (s, 1H) 7.66 (t, J=7.83 Hz, 1H) 7.77 (d, J=7.83 Hz, 1H) 7.98 (d, J=7.83 Hz, 1H) 8.08 (s, 1H) 8.31 (d, J=1.77 Hz, 1H) 8.57-8.61 (m, 1H) 8.59 (d, J=4.55 Hz, 1H) 12.05 (s, 1H). [M+H] calc'd for C28H31N5O2 470; found, 470.4.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[S-:11][C:12]#[N:13].[K+].[I-].[Na+].O>CN(C)C=O>[CH:1]([CH:3]([N:13]=[C:12]=[S:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(N=C=S)c1ccccc1
Temperature: 150 °C

Procedure:
Vinylbenzyl isothiocyanate was prepared in the following manner. 76 g (0.5 moles) of vinylbenzyl chloride were dissolved in 300 ml of dimethylformamide (DMF). To this solution were added 56 g (0.575 moles) of potassium thiocyanate and 28 g (0.187 moles) of sodium iodide. The mixture was heated for 30 minutes at 150°C and then the major portion of DMF was flashed off with a water aspirator vacuum. The solid flask residue was extracted with 750 ml of diethyl ether. The filtered diethyl ether phase yielded 80 g of yellowish liquid. Vacuum distillation gave 30 g (35% yield) of pale yellow vinylbenzyl isothiocyanate liquid, ##SPC9##
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@@H:35]([OH:37])[C@H:34]([N:38]=[N+]=[N-])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@@H:35]([OH:37])[C@H:34]([NH2:38])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@@H](N)[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
Triphenylphosphine (2.13 g, 8.14 mmol) was added to a solution (2R,5R,6R)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (1.65 g, 5.43 mmol) in THF (200 ml) and H2O (0.8 ml), then was heated to 45 degrees C. overnight. The reaction mixture was then diluted with toluene (100 ml×2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et2O and the resulting salt was collected following filtration and was used in the next reaction without further purification (1.7 g, quantitative).
Reaction SMILES: B.C1COCC1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=4)[C:18](=[O:29])[CH:17]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.CCN(CC)CC.CO>C1COCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=4)[C@@H:18]([OH:29])[CH:17]=3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCCOc1ccc2c(c1)C(=O)C=C2c1ccc2c(c1)OCO2
Agent: B
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccc2c(c1)[C@@H](O)C=C2c1ccc2c(c1)OCO2
Temperature: -10 °C

Procedure:
A 100 ml three-necked flask was charged with anhydrous THF (20 mL), (R) -MeCBS catalyst (0.325 mL, 1 M, 0.325 mmol), and BH3-THF (6.49 mL, 1M, 6.49 mmol) under nitrogen. The solution was cooled to −10° C. and 3-(1,3-benzodioxol-5yl)-6-propoxy-1H-inden-1-one (2.0 g, 6.49 mmol) in anhydrous THF (20 mL) was added dropwise over 2 h period. After 45 minutes a solution of Et3N (2.0 mL, 14.3 mmol) and MeOH (1.3 mL, 19.5 mmol) was added cautiously while maintaining the internal temperature below −5° C. The reaction mixture was concentrated in vacuo and purified via flash chromatography (EtOAc/hexane, 1:3) affording (S)-3-(1,3-benzodioxol-5-yl)-6-propoxy-1H-inden-1-ol as a yellow oil (1.9 g, 95%, 94% e.e.); Chiralcel OC column (90:10 IPA/hexane, 2 mL/min, 254 nm): 13.321 min (2.34%) :16.031 min (85.23%); 1H NMR (CDCl3) δ7.30 (d, J=8.3 Hz, 1H), 7.2 (s, 1H), 7.1-7.0 (m, 2H), 6.9 (d, J=8.0 Hz, 1H), 6.8 (dd, J=8.4, 2.4 Hz, 1H), 6.25 H), 6.0 (s, 2H), 5.2 (d, J=7.2 Hz, 1H), 3.95 (t, J=6.6 Hz, 3H), 1.85 (m, 2H), 1.0 (t, J=, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.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>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(OC2CCCCC2)nc1
Reactant: Nc1ncc(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (36.3 mg) was added to a suspension of 3-bromo-5-fluoropyridin-2-amine (200 mg), 6-(cyclohexyloxy)pyridin-3-ylboronic acid (255 mg) and sodium carbonate (222 mg) in DME (5 mL) and water (1 mL) and the mixture was stirred at 90° C. under nitrogen for 3 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (280 mg) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[OH-:7].[Na+].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:23]=[CH:22]C(C#N)=[CH:18][C:17]=2[C:24]([F:27])([F:26])[F:25])[CH2:12][CH2:11]1>O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:23]=[CH:22][C:5]([C:6]([OH:1])=[O:7])=[CH:18][C:17]=2[C:24]([F:27])([F:26])[F:25])[CH2:12][CH2:11]1
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: CN1CCN(c2ccc(C#N)cc2C(F)(F)F)CC1
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc(C(=O)O)cc2C(F)(F)F)CC1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture consisting of 30 mL dioxane, 15 mL water and 11.25 mL of 2M aqueous sodium hydroxide solution is added to 4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)-benzonitrile and the reaction mixture is shaken for 16 hours at 95° C. After cooling, the mixture is evaporated. The resulting residue is treated with water, the pH adjusted to ˜5-6 with 1M hydrochloric acid and the solvent evaporated off under reduced pressure. The residue is treated with hot methanol, the insoluble salt filtered off and the filtrate evaporated yielding the crude title compound which is used for the next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 78 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 8 (49 mg, yield 78%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH3:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH2:14].C(C1C=CC(C=C)=CC=1)C(C)C.[O:27]1[CH2:32]COCC1>[Rh](I)(I)I>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:12])[C:32]([OH:27])=[O:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)O)cc1
Reactant: O
Reactant: C1COCCO1
Agent: I[Rh](I)I
Agent: C=Cc1ccc(CC(C)C)cc1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
A 300-ml autoclave made of Hastelloy was charged with 9.1 g (51.1 mmol) of α-(4-isobutylphenyl) ethyl alcohol, 1.5 g (3.10 mmol) of rhodium iodide, 5.8 g (322 mmol) of water, which gave a concentration of water in the reaction mixture of 2.9 mol/1, and 100 ml of dioxane, as a solvent, to cause a reaction to occur therein under the same conditions as those defined in Example 1. After the completion of the reaction, the gas chromatographic and NMR analysis of the contents indicated that 59% of the α-(4-isobutylphenyl) ethyl alcohol remained unreacted while 40% thereof was converted into 4-isobutylstyrene and α-(4-isobutylphenyl)-propionic acid was formed only in a trace amount.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22](O)=[O:23].[CH:29]1([C:35]2[NH:39][C:38](=[O:40])[C:37]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:35]2[NH:39][C:38](=[O:40])[C:37]3([CH2:41][CH2:42][N:43]([C:22]([C@@H:7]4[CH2:8][C@H:9]([N:11]([CH2:13][C:14]5[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=5[F:21])[CH3:12])[CH2:10][N:6]4[CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)=[O:23])[CH2:44][CH2:45]3)[N:36]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C1NC(C2CCCCC2)=NC12CCNCC2
Reactant: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)O)N(Cc2ccc(Cl)c(Cl)c2)C1
Product: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)N(Cc2ccc(Cl)c(Cl)c2)C1
Yield: 6 %

Procedure:
As described for Example 64e, (2S,4S)-1-(3,4-dichloro-benzyl)-4-[(2,4-difluoro-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one to the title compound (38.8 mg) by preparative HPLC in 6% yield as colorless oil. MS m/e=647.6 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](N)=[CH:8][CH:7]=1.[ClH:15]>O.[Cu](Cl)Cl>[Br:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([Cl:15])=[CH:8][CH:7]=1
Reactant: COc1nc(Br)ccc1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(Br)ccc1Cl
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A solution of sodium nitrite (7.04 g) in water (10 mL) was added dropwise to a suspension of 6-bromo-2-methoxypyridin-3-amine (10.4 g) in concentrated hydrochloric acid (35 mL) under ice-cooling. After stirring for 10 minutes, the reaction system was added dropwise to a suspension of copper chloride (12.7 g) in concentrated hydrochloric acid (15 mL) under ice-cooling, and the mixture was stirred at 65° C. for one hour and 15 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give the title compound as a yellow powder (9.69 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5]2=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)=[CH:7][NH:26][N:25]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2ccc3c(c2)OCCO3)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccc3c(c2)OCCO3)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-hydroxy-chromen-4-one (0.1 g, 0.30 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The quenched reaction was extracted into ethyl acetate (2×30 ml), washed (water), dried (MgSO4), and the solvent remove to give 4-Chloro-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.031 g, 30%); Rf 0.6 Cf SM 0.8 ethyl acetate/hexane (75/25).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:45]
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccn2)nc1C(=O)O
Product: COC1CCN(c2c(NC(=O)c3nc(-c4ccccn4)sc3N)cnn2C)CCC1N

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(pyridin-2-yl)thiazole-4-carboxylic acid gave racemic 322 (58.4 mg, 41% over two steps). 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.54 (d, J=4.7 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.62-7.47 (m, 3H), 7.43-7.31 (m, 1H), 3.64 (s, 3H), 3.27 (s, 3H), 3.23-2.91 (m, 6H), 2.15-2.00 (m, 1H), 1.92-1.80 (m, 1H), 1.79-1.55 (m, 2H). LCMS (ES+) m/z 443 (M+1)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si](C=[N+]=[N-])(C)(C)[CH3:22].CCCCCC>C1COCC1.CO>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:22])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of 5-bromo-2-(2-fluorophenylamino)-3,4-difluorobenzoic acid (30.3 mmol, 11 g) in THF:MeOH (60:20), cooled to 0° C., was added dropwise a solution of 2M TMSCHN2 in hexane (39.39 mmol, 19.7 ml). After the addition is completed, the reaction mixture was warmed to room temperature and stirred for an additional 4 hours. The crude reaction was quenched with acetic acid and extracted with EtOAc. The organic layers are combined, washed with H2O, dry over MgSO4 and concentrated under reduced pressure. The crude material was dried under vacuum and yields to 11 g (96%) of the title product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(=O)c1ccc(F)cc1
Product: CC(=O)c1ccc(Sc2cccc(Br)c2)cc1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in the last paragraph of the portion of Example 66 which is concerned with the preparation of starting materials, 4'-fluoroacetophenone was reacted with 3-bromobenzenethiol to give 4'-(3-bromophenylthio)acetophenone in 82% yield, m.p. 54°-57° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[BH4-].[Na+].[CH2:13](O)[CH3:14]>>[O:8]1[CH:9]=[CH:10][C:6]([CH:1]2[NH:4][CH2:14][CH2:13][NH:3][CH2:2]2)=[CH:7]1
Reactant: CCO
Reactant: C1COCCO1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Product: c1cc(C2CNCCN2)co1
Temperature: 25 °C

Procedure:
To a solution of 6.25 ml of n-butyl lithium in ether at -78° C., under argon, was added 1.46 g of 3-bromofuran. The reaction was stirred at -78° C. for 30 minutes and then a solution of 1.13 g of N-acetyl-N,-O-dimethylhydroxyamine in ether was added. The mixture was stirred for an additional hour at -78° C., then raised to room temperature and quenched with dilute acid. The mixture was extracted several times with ether. The extracts were combined, dried and evaporated, giving 8.88 g of solid. A solution of this solid in 200 ml of dioxane was added to a mixture of 9.99 g of selenium dioxide, 1.62 ml of water and 200 ml of dioxane, which had been heated at 55° C. until a solution formed. This mixture was refluxed for 4 hours, then cooled and filtered through hydrous magnesium silicate. The filtrate was concentrated and purified by silica gel chromatography, eluting with hexane:ethyl acetate (4:1), giving 5.1 g of solid. To a solution of 4.544 g of this solid in 100 ml of ethanol at 0° C., under argon, was added dropwise a solution of 1.8 g of ethylene diamine in 20 ml of ethanol, followed by 10 ml of dioxane. This mixture was stirred at room temperature for 3-hours, then cooled to 0° C. and 2.42 g of sodium borohydride was added. This mixture was stirred at 0° C. for 2 hours, then quenched with water and evaporated. The residue was recrystallized from dichloromethane, giving 3.35 g of 3-(3-furanyl)piperazine.
Reaction SMILES: [I-].[CH3:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH2:5][CH2:6][N+](C)(C)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[S:24])[S-:23])=[N:19][CH:20]=1.C([NH+](CC)CC)C.O>C(#N)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[S:23])[S:24][CH2:6][CH2:5][C:4](=[O:11])[C:3]([CH3:2])([CH3:12])[CH3:13])=[N:19][CH:20]=1
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Reactant: CC(C)(C)C(=O)CC[N+](C)(C)C
Agent: CC[NH+](CC)CC
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 6 h
Yield: 60.1 %

Procedure:
4,4-Dimethyl-3-oxopentyltrimethylammonium iodide (6.0 g) is added, at 20° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (6.1 g) in anhydrous acetonitrile (25 cc). The reaction is allowed to proceed for 6 hours at 20° C. Distilled water (25 cc) is added. The crystals which appear are filtered off, washed three times with distilled water (total 30 cc) and dried in air at 20° C. The product obtained (5.1 g; m.p.=110° C.) is recrystallised from acetonitrile (15 cc). 4,4-Dimethyl-3-oxopentyl 5-chloropyrid-2-yldithiocarbamate (3.8 g), which melts at 111° C., is obtained.