Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[F:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)c(F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 0 °C

Procedure:
To a stirred and cooled (0° C.) solution of 4-bromo-3-fluoroanisole (1 g; 4.88 mmol) in anhydrous THF (7 mL) was added isopropyl magnesium chloride (2.0M in THF; 2.22 mL; 4.43 mmol) dropwise. The reaction was stirred at room temperature for 30 min and then cooled to 0° C. 1-benzyl-4-piperidone (0.72 mL; 4.03 mmol) was added dropwise and the reaction was stirred at room temperature for 14 h. The reaction was quenched with saturated NH4Cl and partitioned between EtOAc (50 mL) and H2O (30 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol as a light orange solid. LCMS =315.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.38-7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 6.66 (dd, J=8.7, 2.5 Hz, 1 H), 6.61 (dd, J=14.4, 2.5 Hz, 1 H), 3.79 (s, 3 H), 3.56 (s, 2 H), 2.77 (br d, J=10.6 Hz, 2 H), 2.54-2.48 (m, 2 H), 2.31-2.24 (m, 2 H), 1.84 (d, J=12.3 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.Br[CH2:30][CH2:31][CH2:32][CH2:33]Br>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N:19]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N3CCCC3)cc12

Procedure:
383 mg of 6-amino-beta-carboline-3-carboxylic-acid-ethylester in 15 ml of ethanol is heated together with 0.58 ml of ethyldiisopropylamine and 0.18 ml of 1,4-dibromobutane for 6 h under nitrogen at the reflux. This is followed by an addition of 0.4 ml of 1,4-dibromobutane and reflux for 3 h. After evaporation, the mixture is washed with water and boiled with ethanol. 128 mg of 6-(1-pyrrolidinyl)-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 259°-261° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]4[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:11]4=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.O.C(O)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]4[CH2:14][CH2:15][NH:16][CH:17]([CH3:18])[C:11]4=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: CC1=NCCn2c1cc1c2-c2ccc(Cl)cc2CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC1NCCn2c1cc1c2-c2ccc(Cl)cc2CC1
Yield: 78 %

Procedure:
3-Chloro-5,6,10,11-tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole (0.9 g) was dissolved in a mixture of 40 ml of methanol and 4 ml of water under argon. The solution was treated portionwise with 0.4 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the solvent was removed in a vacuum, the residue was taken up in 50 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 30 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.9 g of orange solid, was dissolved in a 40-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 1.0 g (78%) of 3-chloro-5,6,8,9,10,11-hexahydro-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 202°- 203° C. (dec.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[C:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[NH:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
tert-Butyl [(1S,2S)-2-aminocyclopentyl]carbamate (900 mg, 4.49 mmol) (purchased from Sigma Aldrich) was taken up in acetonitrile (13 mL). Potassium carbonate (932 mg, 6.74 mmol) and ethyl chloroacetate (0.577 mL, 5.39 mmol) were added, and the resulting mixture was heated to 55° C. overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in EtOAc, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford ethyl N-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}glycinate.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][O:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:18].[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1.O.CCOCC.[Os](=O)(=O)(=O)=O>[CH2:10]([O:9][CH:7]1[CH2:6][O:5][CH:4]([CH2:1][CH:2]=[O:18])[CH2:8]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC1CC(OCc2ccccc2)CO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=CCC1CC(OCc2ccccc2)CO1
Reaction time: 20 h
Yield: 78.7 %

Procedure:
To a stirred solution of 2-allyl-4-(benzyloxy)tetrahydrofuran (3.1 g, 14.20 mmol) in THF (100 mL) and water (100 mL) was added osmium tetroxide (2 mL, 0.327 mmol) at room temperature. After a few minutes, sodium periodate (7.59 g, 35.5 mmol) was added in small portions over 15 min. After 20 h, the reaction mixture was diluted with ether (200 mL), filtered and the filtrate washed with water (2×50 mL) followed by brine (50 mL), then dried (Na2SO4), filtered and concentrated to give a gray oil. Flash column chromatography on a silica gel column using 15-30% ethyl acetate/hexane (5% increment) gave 2-(4-(benzyloxy)tetrahydrofuran-2-yl)acetaldehyde (2.4624 g, 11.18 mmol, 79% yield) as a colorless liquid consisting of a ˜4:1 mixture of diastereomers. 1H NMR (500 MHz, CDCl3) δ: 9.81 (0.8 H, s), 9.77 (0.2 H, s), 7.23-7.37 (5 H, m), 4.48 (1.6 H, s), 4.41 (0.4 H, s), 4.29-4.31 (1 H, m), 4.23-4.20 (0.8 H, m), 4.12-4.09 (0.2 H, m), 4.04-4.06 (0.8 H, m), 3.90-3.94 (0.2 H, m), 3.73 (0.8 H, dd, J=9.9, 4.7 Hz), 3.64 (0.2 H, dd, J=9.9, 4.7 Hz), 2.82-2.94 (1 H, m), 2.60-2.73 (1 H, m), 2.25-2.39 (1 H, m), 1.77 (0.8 H, m), 1.59-1.69 (0.2 H, m). LCMS (M+H) calcd for C13H17O3: 221.12; found: 221.05.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:5]([CH3:9])([OH:8])[C:6]#[CH:7])([CH3:3])=[CH2:2]>CCCCCC.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([CH:4]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:5]([CH3:9])([OH:8])[CH:6]=[CH2:7])([CH3:3])=[CH2:2]
Reactant: C#CC(C)(O)C(CC=C(C)C)C(=C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: C=CC(C)(O)C(CC=C(C)C)C(=C)C
Yield: 95.4 %

Procedure:
A solution of 500 g of 4-isopropenyl-3,7-dimethyl-6-octen-1-yn-3-ol in 1.5 liters of n-hexane was hydrogenated at ambient temperature and atmospheric pressure using 25 g of 0.25% Lindlar catalyst. The reaction was sequentially monitored by gas chromatography (PEG20M, 150° C.) and the reaction was terminated when no starting material remained. The catalyst was filtered off and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was distilled in vacuo to obtain 482 g of 4-isopropenyl-3,7-dimethyl-1,6-octadien-3-ol as a fore-running distillate at bp. 55°-59° C./0.4 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][C:3]=1Br.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:1][C:2]1[C:3]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:22])=[CH:4][C:5]([S:8]([C:11]2[CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CSc1sc(C(N)=O)cc1S(=O)(=O)c1ccc(N)c(Br)c1
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+]
Product: CSc1sc(C(N)=O)cc1S(=O)(=O)c1ccc(N)c(-c2ccccc2C)c1
Yield: 52.1 %

Procedure:
The procedure used in Example 1: step c was followed using 4-(4-amino-3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide ((Example 319: part d) 44 mg, 0.11 mmol), 2-methylphenylboronic acid (54 mg, 0.4 mmol), aq Na2CO3 (2M, 800 μL, 1.6 mmol), and Pd(PPh3)4 (29 mg, 0.025 mmol). Analogous workup and purification by preparative TLC yielded the title compound (24 mg, 56%). 1H-NMR (CDCl3): δ 7.97 (s, 1H), 7.76 (dd, 1H, J=2.3, 8.6 Hz), 7.67 (d, 1H, J=2.3 Hz), 7.32 (m, 2H), 7.28 (m, 1H), 7.16 (m, 1H), 6.76 (d, 1H, J=8.6 Hz), 4.11 (s, 2H), 2.58 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[CH:7][C:6]([C:9](OCC)=[O:10])=[CH:5][N:4]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[N:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of ethyl 2-trifluoromethyl-pyrimidine-5-carboxylate (1 g, 5 mmol) in DCM (23 mL) at −78° C. was added DIBAL-H (6 ml, 6 mmol, 1.0 M solution in toluene) slowly and stirred at the same temperature for 3 h. The mixture was quenched with slow addition of 2M hydrochloric acid and warmed to room temperature. The mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound (572 mg, yield: 71.5%). 1H NMR (CDCl3 400 MHz): δppm 10.27 (s, 1H), 9.35 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1.[C:21]([O:25][C:26](NCC1CN(C(C2C=CC=CC=2)C2C=CC=CC=2)C1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NCC1CN(C(c2ccccc2)c2ccccc2)C1
Product: CC(C)(C)OC(=O)NCCC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from 3-aminoethyl-1-benzhydryl azetidine according the procedure for 3-(N-tert-butyloxycarbonylaminomethyl)-1-benzhydryl azetidine, in a yield of 6.5 g (95%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>C(OCC)C.C(OCC)(=O)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)on1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1cc(-c2ccccc2)on1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of ethyl 5-phenylisoxazole-3-carboxylate (20.0 g) in diethyl ether (50 ml) was added dropwise to a mixture of lithium aluminium hydride (2.62 g) in diethyl ether (50 ml) at 0° C. After stirring for 1 hour, water was added to the reaction mixture carefully, followed by addition of 1N hydrochloric acid (200 ml) and extraction with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain (5-phenyl-3-isoxazolyl)methanol (15.2 g, yield 94%) as pale-brown crystals. m.p. 101-102° C.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([CH3:22])(=[O:21])=[O:20])(=[O:11])=[O:10])=[O:7])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>>[CH3:22][S:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][S:9]([N:8]=[C:6]=[O:7])(=[O:10])=[O:11])(=[O:20])=[O:21]
Reactant: CCCCNC(=O)NS(=O)(=O)Cc1ccccc1S(C)(=O)=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CS(=O)(=O)c1ccccc1CS(=O)(=O)N=C=O
Temperature: 125 °C

Procedure:
A suspension of 5.5 g of the product from Example 9 and 0.1 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) in 100 ml dry xylenes was heated to 125°-130° C. under an atmosphere of nitrogen. At this temperature, 2.5 ml of phosgene was added dropwise at a rate that maintained the temperature above 120° C. After completion of the addition (ca. one hour), the solution was heated at 125° C. for another two hours. After cooling to room temperature, the mixture was filtered under nitrogen and concentrated in vacuo to afford crude 2-(methylsulfonyl)phenylmethanesulfonyl isocyanate as a yellow semisolid which was carried on to the next step without purification. The IR spectrum of this intermediate displayed a characteristic isocyanate absorption at 2240 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:13]([CH:14]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:19][CH:20]=[CH:21][CH2:22]1)=[O:23]
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: COc1ccc([Mg]Br)cc1OC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CC=CCC2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 3,4-dimethoxyphenylmagnesium bromide (59 mmol, 0.29 M) in THF was added dropwise to an ice-cooled solution of cis-1,2,3,6-tetrahydrophthalic anhydride in THF (120 mL) over a 1 h period. After the addition was complete, the resulting mixture was stirred for another 30 min at 0° C. The reaction mixture was allowed to warn to room temperature overnight. The reaction was quenched with sat. NH4Cl(aq) and then the pH was adjusted to 2 with concentrated HCl(aq) and extracted with diethyl ether. The combined organic extracts were washed with water and subsequently extracted with 1 M NaOH(aq). The combined aqueous extracts were neutralized with conc. HCl(aq) and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered through paper, and concentrated under reduced pressure to give an oil. The oil was dissolved in CH2Cl2 and filtered through silica to remove any dicarboxylic acid formed during the reaction work up. The product was recrystallized in diethyl ether to afford a white solid (1.62 g, 5.58 mmol, 10%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:12][CH2:11][C:10](=O)[NH:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:12][CH2:11][CH2:10][NH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1NC(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1NCCCC(N2C(=O)c3ccccc3C2=O)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of [6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3,7-dioxo-[1,2]diazepan-1-yl]-acetic acid tert-butyl ester (4) (775 mg, 2.0 mmol) in THF (4 mL) was added borane-THF complex in THF (1M, 4 mL). The reaction was stirred at 0° C. for 30 min then at room temperature for 3 hours. The mixture was diluted with ice-water (60 mL), extracted with ethyl acetate (60 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a solid, that was purified by flash chromatography using hexane/ethyl acetate (95/5 to 70/30) to afford 585 mg (78% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.43 (s, 9H), 1.78-1.90 (m, 1H), 2.00-2.15 (m, 2H), 2.65-2.78 (m, 1H), 2.95-3.07 (m, 1H), 3.22-3.30 (m, 1H), 3.85-3.92 (d, 1H), 4.30-4.42 (m, 2H), 5.39-5.42 (m, 1H), 7.62-7.71 (m, 2H), 7.79-7.86 (m, 2H). Analytical HPLC: 7.86 min. LC-MS (ES+): m/e=374 (M+H+).
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][NH2:22]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:18]([Cl:17])[CH:19]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2ccc(Cl)c(Cl)c2)c(=O)c1=O
Yield: 42 %

Procedure:
A solution of 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5 mmol, Example 10) and 3,4-dichlorobenzylamine (0.880 g, 5.0 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for approximately 96 hours. The residue isolated after removal of solvent was recrystallized from N,N-dimethylformamide (twice) and from 2-methoxyethanol to provide 0.687 g (42%) of the title compound as a white solid: mp 302°-303° C.; 1H NMR (DMSO-d6) δ 7.77 (m, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 7.33 (m, 1H), 4.71 (d, 2H), 1.35 (s, 9H) ppm. IR (KBr): 3450, 3230, 1800, 1650 cm-1. MS (m/z) 326/328/330 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]([CH3:15])[CH3:14])[C@@:11](O)([C:16]([F:19])([F:18])[F:17])[O:10]C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]([CH:13]([CH3:14])[CH3:15])[C@H:11]([OH:10])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1N(C(=O)OC(C)(C)C)CO[C@]1(O)C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
(4S,5S)-5-Hydroxy-4-isopropyl-5-trifluoromethyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (4.51 g, 0.015 mol) obtained in Example 6 was dissolved in methanol (50 ml), and thereto was slowly added sodium borohydride (500 mg, 0.013 mol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1) and recrystallized from n-hexane/ethyl acetate to give the desired compound (2.1 g, yield: 51%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC>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.CN(C=O)C>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1-c1ccnnc1
Temperature: 118 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 2-(4-bromo-3-methylphenyl)acetate (855 mg, 3.00 mmol), 4-(tributylstannyl)pyridazine (1162 mg, 3.15 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and DMF (10 ml) was stirred under argon atmosphere at 118° C. overnight. After cooled to room temperature, the mixture was concentrated by evaporation of DMF, redissolved in ethyl acetate (50 ml) and washed with water (50 ml×2). After dried over Na2SO4 and concentrated by evaporation, the mixture was subjected to silica gel column chromatography with ethyl acetate/hexanes (1:1) as eluent to give tert-butyl 2-(3-methyl-4-(pyridazin-4-yl)phenyl)acetate 134-2 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26]C)=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH3:25])[N:9]=2)[CH:7]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH3:25])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2cccnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
To a solution of N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (145 mg, 0.379 mmol, 1 eq) in 3.0 mL dichloromethane was added boron tribromide (1.1 mL of a 1.0 M solution in dichloromethane, 1.1 mmol, 2.9 eq). The reaction was stirred at room temperature for 16 hours. The reaction mixture was then quenched with methanol, diluted into ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resulting solid material was triturated with 2 mL DMSO, and the solids collected and dried under vacuum to yield 47.8 mg (34%) of N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=369.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.45 (s, 1H), 9.99 (s, 1H), 9.33 (d, 1H), 8.76 (d, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 7.45 (s, 1H), 7.30 (m, 2H), 7.08 (d, 1H), 3.92 (s, 3H).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH:9]O.[Br:11][C:12]1[S:16][C:15]([CH:17]=[O:18])=[C:14]([CH3:19])[CH:13]=1.[Na]>O.C(#N)C>[Br:11][C:12]1[S:16][C:15]([C:17]([OH:9])=[O:18])=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(Br)sc1C=O
Reactant: OO
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 50.4 g of sodium phosphate, monobasic, (1.5 mol) in 600 mL of water, followed by 131 mL of a 35% hydrogen peroxide solution were added to a solution of 5-bromo-3-methyl-thiophene-2-carbaldehyde (300 g, 1.46 mol), example 1-a, in 1.5 L of acetonitrile. The resultant solution was cooled to 0° C. with an external ice bath, and a solution of 170 g of sodium perchlorite in 2 L of water was added dropwise over a 2 hour period. The reaction mixture was allowed to warm to room temperature, and stirred for 1.5 h. The reaction was quenched with the addition of 10 g of sodium sulfite, and stirred for 15 min. The mixture was acidified to ca. pH 3 with 1 N HCl solution, and cooled to 0° C. An off-white precipitate was collected on a medium glass filter funnel. The precipitate was washed twice with water and then dissolved in ethyl acetate. The aqueous acetonitrile solution was extracted once with ethyl acetate, and the organic fraction was combined with the pervious ethyl acetate solution. The combined organic fractions were dried over anhydrous magnesium sulfate and concentrated under hi-vacuum to produce 305 g of a tan solid. 1H NMR (CDCl3, 200 MHz): δ=6.91 (s, 1H), 2.52 (s, 3H); MS: (−) m/z 218.92, 220.94 (M−1, 79Br/81Br)