Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][N:13](COCC[Si](C)(C)C)[C:9]=2[C:8]([C:22]#[N:23])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][C:26]=2[O:37][CH3:38])[N:6]=1.C(=O)(O)[O-:45].[Na+]>S(=O)(=O)(O)O.O>[Cl:43][C:39]1[CH:40]=[CH:41][CH:42]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[C:8]([C:22]([NH2:23])=[O:45])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][C:26]=2[O:37][CH3:38])[N:6]=1
Reactant: O=C([O-])O
Reactant: COc1cc(CN2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(CN2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C(N)=O
Temperature: 95 °C

Procedure:
To a solution of the product of Example 49C (80 mg, 0.13 mmol) in concentrated sulfuric acid (5 mL) at 0° C. was added water (1 mL) and the mixture was heated to 95° C. for 20 minutes. After cooling, the mixture was diluted with water (3 mL), adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified via preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.00 (br, 1 H), 9.68 (br, 1 H), 8.62 (s, 1 H), 7.85 (d, J=8.4 Hz, 1 H), 7.73 (s, 1 H), 7.61-7.58 (m, 2 H), 7.48-7.42 (m, 1 H), 7.08 (d, J=1.2 Hz, 1 H), 6.62-6.58 (dd, J=8.4, 1.2 Hz, 1 H), 4.75 (s, 2 H), 4.23 (d, 2 H), 3.88 (s, 3 H), 3.44-3.41 (m, 8 H). MS: 525 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C:10]1[C:15]([O:16]COC)=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=1)=[O:9]>C(Cl)Cl>[CH:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=1)=[O:9]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OCOC)c2C=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(O)c2C=O)cn1
Temperature: 25 °C

Procedure:
Neat TFA (1 mL) was added to a DCM solution (3 mL) of ethyl 3-(5-(2-formyl-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (121 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature. After 1 h the resulting mixture was concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH2:15][CH:14]=[CH:13][CH:12]=1)[CH2:8]2.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>C(O)C>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[C:11]1[CH:15]=[CH:14][C:13](=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:12]=1)[CH2:10]2
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1=CCC(C2C3CC4CC(C3)CC2C4)=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1C1C2CC3CC(C2)CC1C3
Reaction time: 120 h
Yield: 71.5 %

Procedure:
A 250 mL round bottom flask was charged with 2-adamantylcyclopentadiene (10.24 g, 51.13 mmol), benzophenone (9.32 g, 51.13 mmol) and 100 mL absolute ethanol. Once the solids had dissolved, sodium methoxide (5.00 g, 92.6 mmol) was added and the reaction was stirred for five days. The orange precipitate was collected by suction filtration and washed with 50 mL ethanol. The air dried product was stirred in 100 methanol overnight and the solid was collected by suction filtration and washed with 50 mL methanol. Drying in vacuo for several hours provided 13.32 grams of desired product (71.5%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:25])[CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:16][CH:17]([CH2:19][N:20]([CH3:25])[CH:21]2[CH2:22][O:23][CH2:24]2)[CH2:18]1
Reactant: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC1CNC1)C1COC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-[(methyl(oxetan-3-yl)amino)methyl]azetidine-1-carboxylic acid tert-butyl ester (330 mg, 1.29 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 1.5 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford (Azetidin-3-ylmethyl)methyl(oxetan-3-yl)amine as colourless oil (180 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 4.64 (2 H, t, J=6.59 Hz), 4.57 (2 H, t, J=6.31 Hz), 3.72 (2 H, t, J=7.87 Hz), 3.58-3.49 (1 H, m), 3.37 (2 H, t, J=7.22 Hz), 2.92-2.82 (1 H, m), 2.44 (3 H, m), 2.06 (3 H, s)
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=[O:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[BH4-].[Na+]>CO>[CH3:3][CH:2]([CH2:4][CH2:5][CH:6]([OH:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:1]
Reactant: CC(C)CCC(=O)CCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC(O)CCC(C)C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A solution of 5.63 g (33 mmol) of 2,8-dimethylnonan-5-one in 150 ml of methanol was cooled to 0° C. and treated with 0.8 g (21 mmol) of sodium borohydride. After 1 h, the solution was quenched with 1N HCl; diluted with 1:1 hexane/ether; washed sequentially with 1N NaOH, water, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 2.30 g (40%) of the desired compound (Rf 0.36, 20% ethyl acetate in hexane) as a colorless oil. 1H NMR (CDCl3) δ 0.88 (d, J=7 Hz, 6H), 0.89 (d, J=7 Hz, 6H), 1.1-1.6 (m, 10H), 3.56 (m, 1H).
Reaction SMILES: S(O[CH2:12][CH2:13][C:14]1([CH3:21])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)(C1C=CC(C)=CC=1)(=O)=O.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:12][CH2:13][C:14]1([CH3:21])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C)COC(C)(C)O2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(CCI)COC(C)(C)O1
Yield: 107.4 %

Procedure:
6.5 g of 4-(2-tosyloxyethyl)-2,2,4-trimethyl-1,3-dioxolane were heated at reflux temperature for 1 hour with 50 g of sodium iodide and 500 ml of acetone, then concentrated, suspended in 100 ml of toluene and filtered. The toluene solution was washed with sodium thiosulphate solution, dried and concentrated. There were obtained 6.0 g (97%) of 4-(2-iodoethyl)-2,2,4-trimethyl-1,3-dioxolane.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:25])[CH2:20][C:21]([NH:23][CH3:24])=O)[N:18]=2)[CH:11]=[CH:12][CH:13]=1.N1C(C)=CC=CC=1C.[C:34]([NH:42][NH2:43])(=O)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:25])[CH2:20][C:21]3[N:23]([CH3:24])[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[N:42][N:43]=3)[N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CNC(=O)CC(C)n1nnc(-c2cccc(Cl)c2)n1
Reactant: NNC(=O)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(Cc1nnc(-c2ccncc2)n1C)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.6 %

Procedure:
Oxalylchloride (2M in DCM, 0.28 mL, 0.55 mmol) was dropwise added during 5 minutes to a solution of 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]-N-methylbutanamide (140 mg, 0.5 mmol) and 2,6-lutidine (0.12 mL, 1 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and isonicotinic acid hydrazide (103 mg, 0.75 mmol) was added. DCM was evaporated after 4 h stirring at r.t. Sat. aq. NaHCO3 (10 mL) was added to the residue and the mixture was refluxed for 16 h. The reaction was allowed to attain r.t., followed by extracted with CHCl3 (3×20 mL). The combined organic phases were dried (MgSO4), concentrated and purified by prep HPLC to yield the title compound (3 mg, 2%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].[C:22]([O:26][C:27](=[O:46])[NH:28][CH2:29][C:30]1[CH:45]=[CH:44][C:33]2[N:34]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[C:35]([CH2:37]Cl)=[N:36][C:32]=2[CH:31]=1)([CH3:25])([CH3:24])[CH3:23].Cl>CN(C=O)C>[C:22]([O:26][C:27](=[O:46])[NH:28][CH2:29][C:30]1[CH:45]=[CH:44][C:33]2[N:34]([CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])[C:35]([CH2:37][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6](=[N:5][O:4][CH2:3][CH2:2][F:1])[C:7]3=[O:15])=[N:36][C:32]=2[CH:31]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: O=C1Nc2ncccc2C1=NOCCF
Reactant: CC(C)CCn1c(CCl)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(CN2C(=O)C(=NOCCF)c3cccnc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Reaction time: 0.33 h
Yield: 72 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine-2,3-dione 3-[O-(2-fluoro-ethyl)-oxime] (23 mg, 0.11 mmol) in DMF (1.6 mL) was added Cs2CO3 (108 mg, 0.33 mmol). After stirring for 20 minutes, [2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester; HCl salt (44 mg, 0.11 mmol) was added and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic fractions washed with water, brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (eluant 1%, 5% MeOH in CH2Cl2) to give [2-[3-(2-fluoro-ethoxyimino)-2-oxo-2,3-dihydro-pyrrolo[2,3-b]pyridin-1-ylmethyl]-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (53 mg, 72%) as an off-white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[F:13]
Reactant: O=c1[nH]ccc2cc(F)c(Cl)cc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Reaction time: 2 h

Procedure:
10 g of 7-chloro-6-fluoro-2H-isoquinolin-1-one (60) were suspended in 100 mL of DMF. 19.75 g of cesium carbonate and 7.55 mL of p-methoxy benzyl chloride were added successively and the mixture was stirred for 2 h. The mixture was poured on ice/water and the formed precipitate was filtered off, washed with water and dried in vacuum to give 13.67 g of the title compound. Rt=1.96 min (Method B). Detected mass: 318.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:5]([N+:20]([O-])=O)[CH:4]=1.Cl[Sn]Cl>C(O)C.O>[NH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)c(N)c1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
2-(4-Methoxy-2-nitrophenyl)-4H-chromen-4-one (1.5 g, 5.04 mmol) was dissolved in ethanol (30 mL) and heated at reflux. SnCl2 (4.97 g 26.23 mmol) was added. The mixture was heated under reflux for 20 min. The reaction mixture was cooled to rt diluted with water, neutralized and extracted with ethyl acetate to give the crude compound. This was purified by column chromatography using 3% MeOH in CH2Cl2 to give 2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (790 mg, 58%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[CH3:9][C:10]1([CH3:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][CH2:12][CH2:11]1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:9][C:10]1([CH3:20])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:1](=[O:3])[CH3:2])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CC1(C)CCOc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
3.4 g of acetyl chloride were dissolved in 30 ml of nitrobenzene and the solution was treated portionwise at 0°-5° C. with 5.7 g of aluminium trichloride. To this mixture was added dropwise at 0°-5° C. a solution of 6.9 g of 4,4-dimethylchromane in 15 ml of nitrobenzene. After stirring for 1 hour, the mixture was poured into ice/water, extracted with ether, the organic phase was washed with 1N sodium hydroxide solution and a saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residual black oil was distilled in a high vacuum. There were obtained 5.1 g of 4,4-dimethyl-6-acetylchromane in the form of a bluish oil of boiling point 110° C./0.02 mmHg.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)([Cl:17])=O>>[OH:1][C:2]1[C:11]([C:12]([Cl:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Product: O=C(Cl)c1cc2ccccc2cc1O

Procedure:
The azo pigments of Formula II listed in FIG. 6 may be prepared, for example, by reacting 2-hydroxy-3-naphthoic acid with thionyl chloride to obtain 2-hydroxy-3-naphthoic acid chloride. Subsequently, the formed acid chloride is added to a solution of N,N-diethylaniline, and an appropriately substituted aniline to yield a coupler compound. A 5 millimole amount of 2,7-diaminodibenzothiophene sulfone is then tetrazotized by an excess amount of a metal nitrite such as sodium nitrite in hydrochloric acid at from about 0° C. to about 30° C., and the product is reacted with HBF4. An 11 millimole amount of the coupler compound previously prepared is then added to the resulting tetrazonium salt in a solution of dimethylformamide at from about 0° C. to about 30° C., followed by the addition of a base, such as sodium acetate in water, to the reaction mixture. The resulting precipitated product is a disazo pigment of Formula II, the specific compound obtained depending on the substituents present in the coupler compound. For example, 3,5-difluoroaniline is selected to obtain the coupler compound 2-hydroxy-3-naphtho-3',5'-difluoroanilide, which is then used to prepare 2,7-bis(1'-azo-2'-hydroxy-3'-naphtho-3",5"-difluoroanilide)dibenzothiophene sulfone. The azo pigments are isolated by filtration and purified by repetitive solvent washings, and may be characterized by elemental analysis, melting point, and IR spectroscopy.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1>C(O)C>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a solution of indole (4.0 g, 34.1 mmol), potassium hydroxide (2.40 g, 42.6 mmol) in ethanol (200 mL) was added and the mixture solution was stirred at room temperature for two hours. The solvent was distilled under reduced pressure. The residue was dissolved in acetone (200 mL), and 1-chloromethyl-4-ethylbenzene (5.28 g, 34.1 mmol) was added thereto. The reaction mixture was stirred at room temperature a whole day and night, and then subjected to Celite filtration and the filtrate was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:500)] to obtain the title compound (3.8 g, 47%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[I-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH3:22]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:9]2[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[CH:20][CH2:21][CH3:22])[C:2]=2[CH3:1])=[O:18])=[CH:12][CH:13]=1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(C=O)cccc1C(=O)c1ccc(F)cc1
Agent: [I-]
Product: CCC=Cc1cccc(C(=O)c2ccc(F)cc2)c1C

Procedure:
Using the procedure of Examples 1 and 2, 2-methyl-3-(p-fluorobenzoyl)-benzaldehyde and n-propyl-triphenyl phosphonium iodide were reacted to obtain 4-fluoro-3'-(butenyl)-2'-methyl-benzophenone which was hydrogenated to form 4-fluoro-3'-(n-butyl)-2'-methyl-benzophenone in the form of an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:14]([C:15]#[N:16])=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[S:23]=S.[NH4+]>CO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:12]=[CH:13][C:14]([C:15](=[S:23])[NH2:16])=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[CH:18]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C#N
Reactant: S=S
Agent: [NH4+]
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(N)=S
Temperature: 60 °C

Procedure:
To a stirred solution of 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinonitrile (19) (30 mg, 0.09 mmol) in MeOH (2 mL), ammonium thiosulfide (5 mL) was added. The reaction mixture was heated at 60° C. in a pressure tube overnight. The reaction mixture was then evaporated to remove excess of solvent. The crude material was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide.
Reaction SMILES: S(C)C.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]([NH:28][C@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][C:4]([CH3:7])([CH:30]([OH:31])[C@H:29]([NH:28][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:32][CH3:33])[CH3:6]
Reactant: [Li]C(C)(C)C
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added tert-butyllithium (1.5 M in pentane, 8.0 mL, 4 eq, 12.0 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −55° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring, and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel gradient column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.57 g (49%). (55% de 3S,4R: 45% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.36 & 0.86 (2×t, 3H, J=7.42 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 0.57 & 0.71 (2×s, 9H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.38-1.52 (m, 2H, —NHCH (CH2CH3)CH(C(CH3)3)OH), 1.99 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.27 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.95 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.22 & 4.77 (2×d, 1H, J=4.42 5.21 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.14-7.52 (m, 15H, 3×Ph).
Reaction SMILES: BrC1C=[CH:14][C:5]2S[C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=3[C:4]=2C=1.CC1(C)C(C)(C)OB(C2C=C(CCC[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])C=CC=2)O1>>[Br:13][C:10]1[CH:9]=[C:8]([CH2:4][CH2:5][CH2:14][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:7]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1ccc2sc3ccc(Br)cc3c2c1
Product: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1

Procedure:
Intermediate 2,8-di(tert-butyl 3-phenylpropylcarbamate)benzothiophene was synthesized by Suzuki reaction of 2,8-dibromodibenzothiophene and tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate, which was obtained from tert-butyl 3-(3-bromophenyl)propylcarbamate. Compound 116 was obtained following similar de-protection reaction condition in route 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]([NH:14][C:15](=[O:20])[C:16](F)(F)F)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[Cl:27][C:28]1[CH:36]=[CH:35]C(C(Cl)=O)=[CH:30][CH:29]=1>O>[Cl:27][C:28]1[CH:36]=[CH:35][C:16]([C:15]([NH:14][C:11]2[CH2:12][CH2:13][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)=[O:20])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C(NC1=NN(c2ccc(Cl)c(Cl)c2)CC1)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1=NN(c2ccc(Cl)c(Cl)c2)CC1)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
A stirred mixture of 2.30 g. of 3-amino-1-(3,4-dichlorophenyl)-2-pyrazoline (prepared as described in Example 1) in 20 ml. of dry pyridine is cooled in an ice bath, then 2.10 g. of p-chlorobenzoyl chloride is added. The reaction mixture is allowed to stand at room temperature for 16 hours then is poured into water to separate a solid. The solid is collected by filtration and dissolved in dichloromethane. This solution is passed through a short column of a hydrous magnesium silicate. The effluent is refluxed and hexane is added until turbidity results. The solution is cooled and filtered to collect a product. The product is recrystallized from the same solvent pair to give 1.8 g. of the desired product as yellow needles, m.p. 177°-178° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][N:5]2[N:4]=1)[CH3:2].[Br:12]Br>CCO>[Br:12][C:11]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: BrBr
Reactant: CCc1cc2n(n1)CCCC2
Solvent: CCO
Product: CCc1nn2c(c1Br)CCCC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-α]pyridine (4.12 g, from Step 2) in EtOH (25 mL) was added Br2 (1.42 mL) dropwise at 0° C. The reaction was stirred at 0° C. for 20 min. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 (saturated). Aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. After concentration, the residue was purified by flash chromatography with 10% EtOAc in hexanes followed by 20% EtOAc in hexanes to give the title compound as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 1.25 (t, 3H, J=7.5 Hz), 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.55-2.70 (m, 4H), 4.07 (t, 2H, J=6.0 Hz).