Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:19])=[O:20])[CH:17]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.25 g (8.76 mmol) of orcinol monohydrate and 2.50 g (8.76 mmol) of 5-bromo-2-methoxybenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.92 g (59%) of the desired product as a pale yellow crystalline solid: 1H-NMR (300 MHz; CDCl3) δ 7.93 (d, 1 H, J=2.5 Hz), 7.69 (dd, 1 H, J=8.9, 2.5 Hz), 6.98 (d, 1 H, J=8.9 Hz), 6.54 (br s, 1 H), 6.51 (br s, 1 H), 6.41 (t, 1 H, J=2.2 Hz), 3.98 (s, 3 H) and 2.24 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:35]3[CH2:34][CH2:33][N:32]([C:26]4[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=4[CH3:24])[CH2:37][CH2:36]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2-c2ccccc2)cc1

Procedure:
104 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 1-(2,4-dimethylphenyl)piperazine (50 mg, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:15]([O:17][CH3:18])=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>C1COCC1>[CH2:31]([C:7]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:15]([O:17][CH3:18])=[O:16])[CH:1]=2)[CH2:6]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(c1)CCC(C(=O)OC)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCc2cc(C(=O)OC)ccc2C1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-dimethyl 1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate from Step A (10.0 g, 40.4 mmol) in THF (200 mL) at −70° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 45 mL, 45 mmol) dropwise, over 10 min, such that the reaction temperature was maintained below −65° C. during the addition. The mixture was stirred at −70° C. for a further 40 min, then allyl bromide (5.87 g, 48.5 mmol) was added dropwise over 3 min. Stirring was continued at −70° C. for 2 h, then the mixture was partitioned between H2O (300 mL) and EtOAc (300 mL). The aqueous phase was extracted further with EtOAc (2×300 mL), and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH3:12]>>[NH2:12][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: N
Product: Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
Into an autoclave made of SUS-316 and having an internal capacity of 2 l, 363 g (2.0 mols) of 2-chloro-5-trifluoromethylpyridine, 19.8 g (0.2 mol) of cuprous chloride and 1,275 g (30.0 mols as NH3) of 40% aqueous ammonia were added, and the reaction was carried out at 120° C. for 16 hours under heating with stirring. After completion of the reaction, the reaction mixture was cooled to room temperature and separated into an aqueous ammonia layer and an oil layer, whereby 335 g of an oil containing 1.5% of the starting material 2-chloro-5-trifluoromethylpyridine and 91% of 2-amino-5-trifluoromethylpyridine (as analyzed by liquid chromatography) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2cc(Br)ccn2)cc1

Procedure:
In a manner similar to that describe in Preparation 34, 4-bromo-pyridine-2-carboxylic acid and 4-isopropylaniline were converted to the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=CC(S(O)(=O)=O)=CC=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.[C:30](=[O:33])([O-])[O-].[Na+].[Na+].S(O)(=O)(C1C=CC=C(N)C=1)=O>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:33][CH3:30])=[CH:4][C:3]=1[S:17]([OH:20])(=[O:18])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Agent: Fc1nnnc(F)c1F
Agent: Nc1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: O
Product: COc1ccc(N)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
31.9 g of 2-amino-5-hydroxy-naphthalene-1,7-disulphonic acid are dissolved in 400 ml of water to give a neutral solution. 300 g of ice are then added, and 8.8 ml of trifluorotriazine are allowed to run in, a pH of 4.0-4.5 being maintained with 15% strength sodium carbonate solution. The mixture is subsequently stirred for 5 minutes, a neutral solution of 17.3 g of m-sulphanilic acid is then added, and a pH of 5.0-5.5 is maintained with 15% strength sodium carbonate solution. During the acylation, the temperature is allowed to rise to 15°-20°. A diazo compound obtained by the customary route by diazotisation of 20.3 g of 1-amino-4-methoxy-benzene-2-sulphonic acid is added to the resulting solution of the reaction product of the formula ##STR17## at 5°-10°, the pH simultaneously being kept at pH 7.0-7.5 by sprinkling in sodium bicarbonate. When the coupling has ended, the dyestuff of the formula ##STR18## is salted out, filtered off with suction, dried and ground. The red dyestuff powder dissolves readily in water and dyes cotton a clear scarlet (colour code number 6) by a process customary for reactive dyestuffs.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH3:16][C:17]([CH3:23])([CH3:22])[CH:18]=[CH:19][CH:20]=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:17]([CH3:23])([CH3:22])[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: C=CC=CC(C)(C)C
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1COc1cncc(C=CC=CC(C)(C)C)c1
Temperature: 100 °C
Yield: 75 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272 mg, 3.0 mmol) in acetonitrile (3.0 mL) and triethylamine (2.5 mL) was added 5,5-dimethyl-1,3-hexadiene (0.50 mL), palladium acetate (23.0 mg, 0.1 mmol) and tri-o-tolylphosphine (122 mg, 0.1 mmol). After being heated in a sealed tube at 100° C. overnight, the resulting mixture was cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3 /MeOH 10:1 to afford a light yellowish oil (225 mg, 75%). MS (CI/NH3) m/z 301 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.08 (S, 9H), 1.55-1.77 (m, 3H), 1.98-2.10 (m, 1H), 2.37-2.47 (m, 1H), 2.50 (s, 3H), 2.64-2.73 (m, 1H), 3.07-3.17 (m, 1H), 3.90-4.06 (m, 2H), 5.93 (d, J=15.5 Hz, 1H), 6.16 (dd, J=15.5, 9.9 Hz, 1H), 6.42 (d, J=15.5 Hz, 1H), 6.78 (dd, J=9.9, 15.5 Hz, 1H), 7.21 (dd, J=3.0, 1.5 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H), 8.19 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6]([C:9]([CH3:11])=O)([CH3:8])=[CH2:7]>[OH-].[Na+]>[CH3:7][C:6]1([CH3:8])[CH2:3][CH:2]([CH3:4])[C:1](=[O:5])[CH:11]=[CH:9]1
Reactant: C=C(C)C(C)=O
Reactant: CC(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(C)(C)C=CC1=O
Yield: 43 %

Procedure:
To a mixture of isobutyraldehyde (382 g, 5.3 mole) in 400 ml of 0.8 M aqueous sodium hydroxide was added methyl isopropenyl ketone (420 g, 5.0 mole) over a 1 hr period at 25°. The mixture was then heated to 75° for 1 hr. The mixture was cooled, and the layers were separated. The organic phase was washed neutral with water. Distillation of this organic material afforded 297 g (2.15 mole, 43% yield) of the desired 4,4,6-trimethyl-2-cyclohexenone, bp 68°-69° at 10mm, nD20 1.4685, with an infrared and nmr spectra identical with that reported in the literature (JOC 33, 4060 (1968)). Continued distillation afforded a new material (116 g) with a boiling point of 100° to 120° at 0.5mm. This material slowly crystallized and was filtered and washed with hexane. These crystals proved to be 5-hydroxy-2,4,4-trimethylcyclohexanone and exhibited the following spectral characteristics: mp 105°-106°; ir (KBr) 3360 (OH), 1685 (C=O), 1250, 1195, 1135, 1111, 1029, 983 cm-1 ; nmr (CDCl3) 0.98 (d, J=6.5Hz, 3H), 1.04 (s, 3H), 1.22 (s, 3H), 1.53 (d,d,d, J=13, 8, 1.5 Hz, 1H), 1.90 (d, J=13 Hz, 1H), 2.35 (d,d, J=15, 3 Hz, 1H), 2.62 (d,d, J=15, 3 Hz, 1H), 3.85 (m, 1H); mass spectrum (m/e, (relative intensity) 156 (8), 138 (2), 100 (100), 72 (35), 70 (33) 68 (37), 56 (80), 43 (38), 41 (37).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:13]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Cl)n1
Product: O=C(Cl)c1cccc(Cl)n1

Procedure:
A mixture of 40 g 6-chloro-2-pyridinecarboxilic acid and 150 ml SOCl2 is refluxed 4 hrs. After removing excess SOCl2 there is obtained 44 g 6-chloro-2-pyridinecarboxylic acid chloride, m.p. 76° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)/[CH:15]=[CH:16]/[CH3:17])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:14]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)/[CH:15]=[CH:16]/[CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C=C/[C@@H](c1ccc(-c2ccc(F)cc2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C/C=C/[C@@H](c1ccc(-c2ccc(F)cc2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
A solution of the product from Step E (3.55 g, 8.9 mmol) in 250 mL of 3:1:1 tetrahydrofuran/methanol/1N aqueous lithium hydroxide solution (50 mL, 50 mmol) was stirred at room temperature for 15 h then concentrated and acidified with 200 mL of 10% aqueous hydrochloric acid. The resultant mixture was then extracted with three 150-mL portions of ethyl acetate, the organic phases combined and washed sequentially with 5% hydrochloric acid and saturated aqueous brine (100 mL each). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the acid as a colorless foamy solid that was used without further purification. LC/MS 385.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:25])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccc(F)cc2C2CCCC12
Product: Fc1ccc2c(c1)C1CCCC1C(=S)N2
Yield: 79.7 %

Procedure:
Analogously to Example 4, 8-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (280 mg, 1.36 mmol) is reacted with Lawesson's reagent (608 mg, 1.5 mmol) to form 240 mg (80%) of product.
Reaction SMILES: C[O:2][C:3]([C:5]1(C(OC)=O)[CH:7]([CH2:8][C:9](Cl)([Cl:11])[Cl:10])[C:6]1([CH3:14])[CH3:13])=[O:4].[OH-].[Na+]>CO>[Cl:10][C:9]([Cl:11])=[CH:8][CH:7]1[CH:5]([C:3]([OH:4])=[O:2])[C:6]1([CH3:13])[CH3:14]
Reactant: COC(=O)C1(C(=O)OC)C(CC(Cl)(Cl)Cl)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 1,1-dimethoxycarbonyl-2,2-di-methyl-3-(2,2,2-trichloroethyl)cyclopropane (8.7 g, 27.3 mmoles) prepared according to the procedure of Example 5, methanol (8 ml) and 20 percent aqueous NaOH (35 ml, 175 mmoles) is heated at 100° C. for 5 hours. Acidification of the solution with concentrated HCl precipitates 2(2,2-dichlorovinyl)-3,3-dimethylcyclopropane dicarboxylic acid (6.44 g, 93 percent) which is subjected to bulb-to-bulb distillation at 0.3 mm Hg, 110° C.-150° C. The monoacid, 2(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylic acid (5.31 g), distills as it is formed from decarboxylation in about 100 percent yield. The structure of the monoacid is confirmed by its infrared and nuclear magnetic resonance spectra.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:3]=12.[OH-].[K+].[CH2:22](O)[CH3:23].C(I)C>O>[CH2:22]([N:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2](=[O:1])[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]1=2)[CH3:23]
Reactant: CCO
Reactant: CCOC(=O)c1cnc2sc3c(c2c1O)CCCC3
Agent: [K+]
Agent: [OH-]
Solvent: CCI
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c3c(sc21)CCCC3

Procedure:
A mixture of 1.38 parts of ethyl 4-hydroxy-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carboxylate, 11 parts by volume of 10 % aqueous potassium hydroxide, 44 parts by volume of ethanol and 45 parts by volume of water and 1.5 parts by volume of ethyl iodide is refluxed for 4 hours and the product is isolated in a manner similar to that described in Example 13, whereby 1-ethyl-1,4,5,6,7,8-hexahydro-4-oxo[1]benzothieno[2,3-b]pyridine-3-carboxylic acid is obtained as crystals. Recrytallization from ethanol and, then, from tetrahydrofuran gives colorless needles melting at 218°-221°C.
Reaction SMILES: [OH:1][CH:2]1C(O)(S(O)(=O)=O)[CH2:6][CH2:5][O:4][CH2:3]1.[Na].CO[CH:16]([O:19][CH3:20])[O:17][CH3:18]>CO>[CH3:20][O:19][C:16]1([O:17][CH3:18])[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[OH:1]
Reactant: COC(OC)OC
Reactant: O=S(=O)(O)C1(O)CCOCC1O
Agent: [Na]
Solvent: CO
Product: COC1(OC)CCOCC1O

Procedure:
reacting said 3,4-dihydroxytetrahydro-2H-pyran-4-sulfonic acid, sodium salt with methanol and trimethylorthoformate in the presence of an acid to form 4,4-dimethoxytetrahydro-2H-pyran-3-ol; and
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH2:15]([CH2:25]/[C:26](/[CH3:35])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:34])=[CH:31]/[CH2:32]Br)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C=O)C>[CH3:34]/[C:30](/[CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:35])/[CH2:25][CH2:15]/[CH:16]=[C:17](\[CH3:18])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:31]\[CH2:32][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Reactant: O=c1ccc2cc(O)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (474 mg, 2.92 mmol) and 4 mL of anhydrous DMF were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (117 mg of 60% mineral oil suspension, 2.93 mmol) was added and the solution was stirred at 0° C. for 30 minutes. The crude geranylgeranyl bromide (302.85 mg) from the previous step was dissolved in anhydrous DMF, cooled to 0° C. and added drop-wise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired compound was isolated via preparative thin layer chromatography using a 7:3 Hexanes:Ethyl acetate solvent system. The purified product was characterized by 1H-NMR spectroscopy and high-resolution mass spectrometry (HRMS). 1H-NMR (300 MHz, CD3COCD3): δ 1.54-1.75 (15H), 1.93 (m, 12H), 4.65 (2H), 5.09 (3H), 5.53 (1H), 6.40 (1H), 7.11 (3H), 7.81 (1H). HRMS (EI) Calcd. for C79H38O3: 434.28210. found: 434.28236.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Nc3ccc(C#N)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 341(MH+). 1H NMR(DMSO): δ 2.26(s, 3H), δ 5.82(s, 1H), δ 6.52(m, 1H), δ 7.25(t, 1H), δ 7.35(br, 1H), δ 7.55(m, 2H), δ 7.71(d, 2H), δ 8.22(d,2H), δ 8.32(d, 1H), δ 8.79(s, 1H), δ 9.47(s,1H), δ 11.75(s, 1H).
Reaction SMILES: F[C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5].[OH-].[NH4+:35]>>[NH2:35][C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3F)cc3ccccc23)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3N)cc3ccccc23)CC1
Temperature: 110 °C
Yield: 24 %

Procedure:
A microwave vial was charged with tert-butyl 4-(3-(2-fluoronicotinoyl)isoquinolin-1-yl)-1,4-diazepane-1-carboxylate (78 mg, 0.17 mmol) and a saturated aqueous solution of ammonium hydroxide (2 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 25 minutes. The mixture was cooled down to room temperature, partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (18 mg, 24% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[S:14])[NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][C:17]([CH2:19]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[S:14][CH:19]=[C:17]([CH2:16][Cl:15])[N:13]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=S)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nc(CCl)cs2)C1

Procedure:
To a solution of 3-Thiocarbamoyl-azetidine-1-carboxylic acid tert-butyl ester (0.800 g, 3.7 mmol) in acetone (15 mL) was added 1,3-dichloroacetone (0.611 g, 4.81 mmol), MgSO4 (0.67 g, 5.6 mmol) and MgCO3 (3.12 g, 3.7 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (20 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product which was used without further purification.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][CH3:16])=[CH:10][N:9]=1.[F:17][C:18]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[NH:28][C@H:29]1[CH2:33][CH2:32][N:31]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:30]1=[O:40].C1(C)C=CC=CC=1>CCOC(C)=O.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]>[CH2:15]([C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([N:37]2[CH2:36][CH2:35][CH:34]([N:31]3[CH2:32][CH2:33][CH:29]([NH:28][C:19]4[CH:20]=[CH:21][C:22]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:23][C:18]=4[F:17])[C:30]3=[O:40])[CH2:39][CH2:38]2)=[N:9][CH:10]=1)[CH3:16]
Reactant: CCc1cnc(Cl)c(C)c1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cnc(N2CCC(N3CCC(Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(C)c1
Temperature: 110 °C
Yield: 23.4 %

Procedure:
To a nitrogen purged reaction vessel was added Pd2 dba3 (0.0129 g, 0.0141 mmol), Cs2CO3 (0.229 g, 0.703 mmol), Binap-rac (0.035 g, 0.0563 mmol), 2-chloro-5-ethyl-3-methylpyridine (0.037 g, 0.234 mmol) and (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 0.100 g, 0.281 mmol). Toluene (3 mL, purged with nitrogen) was added and the reaction was heated at 110° C. overnight. The reaction was cooled to ambient temperature, diluted with EtOAc and washed with water. The combined organic layers were dried over Na2SO4 and purified by preparative HPLC (Parallex Flex) to give 1-(1-(5-ethyl-3-methylpyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.026 g, 23% yield) as white solids. Mass spectrum (apci) m/z=475.3 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:11])=[CH:8][C:7]=1[O:24][CH3:25]>>[OH:5][C:6]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)=[O:11])=[CH:8][C:7]=1[O:24][CH3:25]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)ccc1O
Product: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3.2 ml of 65 percent nitric acid are added dropwise within 10 minutes at 20° to 12.8 g of 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in 160 ml of acetic acid). After stirring for 1.5 hours, the reaction mixture is poured into 600 ml of ice-water, and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone of melting point 172°.