Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[CH2:15][C:16]1[N:17]([CH3:42])[C:18]2[C:23]([N:24]=1)=[C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:21]=[C:20]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH2:40][CH3:41])[N:19]=2.Cl[CH2:44][C:45]([NH2:47])=[O:46]>C(Cl)Cl>[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([CH2:15][N:9]4[CH2:10][C@@H:11]5[CH2:14][C@H:8]4[CH2:13][N:12]5[CH2:44][C:45]([NH2:47])=[O:46])[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Reactant: NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4CC(N)=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
Triethylamine (85 μL, 0.61 mmol) was added to a solution of 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (250 mg, 0.53 mmol) and 2-chloroacetamide (60 mg, 0.64 mmol) in DCM (10 mL) The mixture was stirred at ambient temperature for 24 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 99:1 to 98:2) to afford 597 as a cream solid (175 mg, 62%). LCMS (method I): RT=2.35 min, M+H+=531. 1H NMR (CDCl3, 400 MHz) δ 12.12 (bs, 1 H), 8.01 (m, 1 H), 7.77 (m, 1 H), 7.26 (m, 2 H), 5.62 (bs, 1 H), 4.34 (m, 4 H), 3.92-3.83 (m, 9 H), 3.54 (m, 2 H), 3.37 (q, J=7.4 Hz, 2 H), 3.09 (m, 4 H), 2.93 (m, 2 H), 2.00 (m, 2 H) and 1.42 (t, J=7.4 Hz, 3 H)
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])[S:15][CH3:16])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[N:17][C:26](=[O:27])[O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH3:16])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: I
Solvent: C1CCOC1
Product: CSC(=NC(=O)OCc1ccccc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 66 °C

Procedure:
To a stirred solution of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea hydroiodide (Intermediate I) (50 g, 0.129 mol) in dry THF (1 L) is added TEA (18 mL, 0.129 mol), followed by N-(benzyloxycarbonyloxy)-succinimide (32.1 g, 0.129 mol). The reaction mixture is then heated to reflux (66° C.) for 6 hours. The reaction is allowed to cool to room temperature, then concentrated in vacuo to a yellow solid. The crude is suspended in EtOAc (500 mL) and water (500 mL) and is triturated vigorously for a period of 30 minutes. The resulting suspension is filtered and dried in a vacuum oven (40° C.) over P2O5 to give the product as a pale yellow solid. [M+H]+ 395
Reaction SMILES: C([Li])CCC.[CH2:6]([N:10]1[CH:14]=[N:13][N:12]=[N:11]1)[CH2:7][CH2:8][CH3:9].[I:15]I.O>O1CCCC1>[I:15][C:14]1[N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[N:11]=[N:12][N:13]=1
Reactant: II
Reactant: CCCCn1cnnn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1nnnc1I
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of inert gas, 0.032 mol (20 ml) of butyllithium (1.6M in hexane) is added dropwise to a solution, cooled to −78° C., of 0.03 mol (3.78 g) of 1-butyltetrazole in 40 ml of anhydrous tetrahydrofuran such that the temperature of the reaction mixture does not exceed −70° C. The mixture is stirred at this temperature for 30 minutes, and 0.03 mol (7.61 g) of iodine in 10 ml of anhydrous tetrahydrofuran is then added dropwise. After 30 minutes of stirring at this temperature, the reaction mixture is warmed to −30° C., and 1 ml of water is added carefully. The solvent is distilled off under reduced pressure and the residue is taken up in ethyl acetate/water. The aqueous phase is extracted with ethyl acetate and the combined organic phase is washed with sodium thiosulfate solution and saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after distillative removal of solvent under reduced pressure is purified chromatographically (mobile phase: chloroform). This gives 2.2 g (30%) of 5-iodo-1-butyltetrazole
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH2:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[NH:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)=[O:32].C=O.[C:41](O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH2:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][N:25]3[CH3:41])=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[NH:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)=[O:32]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3)c3cc(NC(=O)c4ccncn4)c(Cl)cc3[nH]c2=O)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C)c3cc(NC(=O)c4ccncn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of pyrimidine-4-carboxylic acid (S)-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-amide (prepared essentially as described in EXAMPLE 2, 9 mg in 0.40 mL methanol) was added 6 mg paraformaldehyde followed by 20 mg powdered 4A molecular sieves and 0.01 mL acetic acid and the mixture stirred at room temperature for 10 minutes. At this time, 5 mg sodium cyanoborohydride was added and the stirring continued. After 2 hours, 0.5 mL tetrahydrofuran was added to ensure homogeneity and after 60 hours the reaction was quenched by the addition of water. The reaction mixture was extracted with methylene chloride and the combined organics washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 92:8) gave the title compound (6.7 mg). MASS: 546 (M+H) ##STR167##
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:25].[CH3:26][O:27][NH2:28].C(O)C.Cl>C(OCC)C>[ClH:25].[CH3:26][O:27][N:28]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:21][O:22][CH2:23][CH3:24])[CH3:19]
Reactant: CON
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NOC

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-methylhydroxylamine hydrochloride. The product was dissolved a mixture of ethanol and diethyl ether, and a solution of hydrogen chloride (1 equivalent of a 1.0 M solution in diethyl ether) was added. A precipitate formed, and the solvents were removed under reduced pressure. The resulting solid was recrystallized from a mixture of ethanol and diethyl ether to provide 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime hydrochloride in about a 6.4 to 1 mixture of E and Z isomers as a white solid, mp 189-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:3]=1C=O.[NH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:3]=1[NH:28][CH2:29][CH2:30][NH:31][C:32]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:38]
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(C=O)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Br
Temperature: 25 °C

Procedure:
The product from Example 1, Step A (1 eq) and tert-butyl N-(2-aminoethyl)carbamate (3 eq) are dissolved in methanol, to which sodium cyanoborohydride (1.5 eq) is added in portions at 0° C. The reaction is stirred at room temperature until complete, and then quenched by the addition of saturated aqueous ammonium chloride and stirred until hydrogen evolution ceases. The resulting suspension is concentrated in vacuo and then partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers are separated and the aqueous layer is extracted with methylene chloride. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel with ethyl acetate and hexane to provide the title product.
Reaction SMILES: [C:1]1([CH:7]2[CH2:24][NH:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO>[CH2:25]([N:23]1[CH2:24][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH2:22]1)[CH3:26]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1CC(c2ccccc2)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (735 mg, 2.21 mmol) in methanol (10 mL) was added acetaldehyde (107 mg, 136 μL, 2.43 mmol), then sodium cyanoborohydride (195 mg, 1.5 mL, 3.10 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with DCM (50 mL), washed with 1:1 aq. sat. NaHCO3/25% NaOH (10 mL), and the aqueous layer was extracted with DCM (2×25 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography using (0-75% EtOAc/DCM) as eluent to give tert-butyl 8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (540 mg, 68%) as a viscous yellow oil. ESI-MS m/z calc. 360.5. Found 361.7 (M+1)+; Retention time: 1.15 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].O[CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[N:28]1[CH3:37]>C1(C)C=CC=CC=1>[CH3:37][N:28]1[C:29](=[O:36])[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]1[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)c2ccccc2C1O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2ccccc2C(=O)N1C
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
11.5 g of ethoxycarbonylmethylenetriphenylphosphorane are added to a suspension of 4.5 g of 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one in 110 cm3 of toluene. The reaction mixture is refluxed with stirring for 16 hours and then cooled to a temperature in the region of 20° C. The mixture is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residual oil is taken up in 50 cm3 of diethyl ether. The precipitate formed is filtered off and then washed twice with 10 cm3 of diethyl ether. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. to give an orange-colored oil, which is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 20-45 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (70/30, 65135, 60/40 by volume). The fractions comprising the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature in the region of 30° C. 4.1 g of ethyl (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a yellow oil. (Rf=0.25, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1.[CH3:17]I>>[CH3:17][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1
Reactant: O=C1Cc2c(cccc2C2CCCNC2)N1
Reactant: CI
Product: CN1CCCC(c2cccc3c2CC(=O)N3)C1

Procedure:
Using the procedure of Example 3, 1,3-dihydro-4-(piperidin-3-yl)-2H-indole-2-one and methyl iodide were reacted to obtain 1,3-dihydro-4-(1-methyl-piperidin-3-yl)-2H-indole-2-one which melted at 160° C. after crystallization from benzene.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:13])=CN(C)C)=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1.O1CCOCC1>O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:13])=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1
Reactant: Cc1ccsc1C(=O)C(=CN(C)C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccsc1C(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 34.7 %

Procedure:
A stirred solution of 6.4 g of 4-trifluoromethyl-β-(dimethylamino)-α-(3-methyl-2-thienoyl)-2-nitrostyrene, 49 ml of 1,4-dioxane, and 10 ml of water was refluxed for 42 hr. The cooled solution was concentrated, and the residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue crystallized upon standing at room temperature. The solid was recrystallized from 95% ethanol to afford 1.9 g (35%) of product, mp 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([C:19]#[C:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1.[H][H]>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([CH2:19][CH2:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1
Reactant: [H][H]
Reactant: COc1ccc(CNc2nnc(C#CC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(CCC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Yield: 57.4 %

Procedure:
690 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)-1-ethynyl]-6-phthalazine carbonitrile was dissolved in 200 ml tetrahydrofuran, 50 mg of 10% Pd—C was added thereto, and the mixture was stirred for 0.5 hr in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography to give 400 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)ethyl]-6-phthalazine carbonitrile. This product was converted in a usual manner into the hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](\Br)/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Zn]CC)[CH3:26]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)\[CH2:25][CH3:26])[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C(\Br)c2ccc(Cl)cc2)COC1(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred solution of (S)-4-[(Z)-2-bromo-2-(4-chloro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.04 g) in THF (8 ml) were added bis(tri-tert-butylphosphine)dipalladium (0) (64 mg) and diethylzinc (4.99 ml, 1.1 M solution in toluene). The mixture was stirred at r.t. for 90 min then was diluted with ethyl acetate and washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[(E)-2-(4-chloro-phenyl)-but-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (824 mg, 90%) as a colourless oil. MS (ISP): 368.5 ([{37Cl}M+H]+), 366.5 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[C:21]([NH:32][CH:33]4[CH2:38][CH2:37][N:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:35][CH2:34]4)[N:22](COCC[Si](C)(C)C)[N:23]=3)[N:9]=[C:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:11]=2[CH:12]=1)#[N:2].S(=O)(=O)(O)[OH:44].N>C1(C)C=CC=CC=1>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[C:10]1[C:11]2[CH:12]=[C:3]([C:1]([NH2:2])=[O:44])[CH:4]=[CH:5][C:6]=2[C:7]2=[N:23][NH:22][C:21]([NH:32][CH:33]3[CH2:34][CH2:35][N:36]([S:39](=[O:41])(=[O:40])[NH2:42])[CH2:37][CH2:38]3)=[C:8]2[N:9]=1
Reactant: O=S(=O)(O)O
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(C#N)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Agent: N
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(N)(=O)=O)CC3)[nH]nc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
54 mg of 4-{[7-cyano-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide are introduced into 0.5 ml of toluene. After cooling to 0° C. using an ice bath, 90 μl of 95% sulphuric acid are added and the mixture is stirred at RT for 24 h. It is cooled to 0° C. and neutralized with 9 ml of 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (95/05 by volume). This gives 7 mg of 5-(2,6-difluorophenyl)-3-[(1-sulphamoylpiperidin-4-yl)amino]-2H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (yellow solid). 1H NMR: 1.67 (m, 2 H) 2.11 (m, 2 H) 2.67 (m, 2 H) 3.47 (m, 2 H) 3.71 (m, 1 H) 6.01 (d, J=8.2 Hz, 1 H) 6.70 (broad s, 2 H) 7.33 (t, J=7.7 Hz, 2 H) 7.55 (broad s, 1 H) 7.68 (m, 1 H) 8.17 (broad s, 1 H) 8.22 (broad s, 1 H) 8.35 (broad d, J=8.5 Hz, 1 H) 8.45 (d, J=8.5 Hz, 1 H) 12.84 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27]CC)=[O:26].[OH-].[K+]>CN(C)C=O.O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:10](=[O:16])[CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:4]=[CH:5][C:6]=1[O:9][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)CC(=O)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2',3'-dichloro-3,3-dimethyl-4'-hydroxybutyrophenone (15.5 g., 0.059 mole) and potassium carbonate (9.7 g., 0.070 mole) in dimethylformamide (DMF) (60 ml.) is stirred at 65° C. for 1/2 hour. Ethyl bromoacetate (11.7 g., 0.070 mole) is added in one portion and heating and stirring were continued for three hours. A solution of potassium hydroxide (4.6 g., 0.082 mole) in water (80 ml.) is added and the mixture is refluxed for 1/2 hour. The resulting semisolid mass is added to water (750 ml.). The solution is heated to boiling, filtered, cooled and acidified (HCl) to afford 18 g. of [2,3-dichloro-4-(3,3-dimethylbutyryl)phenoxy]acetic acid, m.p. 145°-145.5° C. after recrystallization from benzene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH:19]([CH3:21])[CH3:20])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)(=[O:8])=[O:7].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:31]([O:32][CH3:33])=[C:28]([O:29][CH3:30])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][N:23]([CH3:22])[CH2:2][CH2:3][CH2:4][N:5]([CH:19]([CH3:21])[CH3:20])[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)(=[O:8])=[O:7])[CH:35]=[CH:34][C:31]=1[O:32][CH3:33]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(C)N(CCCCl)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1ccc(CCN(C)CCCN(C(C)C)S(=O)(=O)c2cccc(C(F)(F)F)c2)cc1OC
Reaction time: 48 h

Procedure:
N-(3-chloropropyl)-N-(1-methylethyl)-3-trifluoromethylbenzenesulfonamide (23.4 g, 0.068 mol) and N-methylhomoveratrylamine (13.29 g, 0.068 mol) in xylene (250 mL) containing anhydrous potassium carbonate (4.68 g, 0.034 mol) and cesium carbonate (11.08 g, 0.034 mol) were heated and stirred for 21/2 days. The reaction was cooled, filtered and stripped to provide a gum with a small amount of crystalline material evident. Solution in diethyl ether, filtration of the small amount of solid and concentration of the filtrate provided the crude product (32.91 g). Chromatography first on dry column alumina then silica gel provided the same product as in the preceding example (11.84 g) as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[C:4]([Br:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Br:10])[C:5]=1[O:9][CH3:11])[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Br)c(O)c(Br)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)cc(N)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-2,6-dibromo-phenol (14.13 g, 52.9 mmol) was dissolved in acetone (425 mL) to give a dark brown solution. Potassium carbonate (21.95 g, 158.8 mmol) was added followed by iodomethane (3.46 mL, 55.6 mmol). The mixture was stirred at rt overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. Sodium metabisulphite and brine were added to aid separation of the layers. The mixture was extracted into EtOAc (4×150 mL). The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) then brine, dried over Na2SO4 and concentrated under reduced pressure. A dark brown oil was obtained which crystallised upon standing. The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a brown solid, 11.31 g (76%). m/z: 280.03/282.00/284.02 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]([CH3:17])([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O.Cl.C(N)C.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH2:2][CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]([CH3:16])([CH3:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CC(N)=O
Agent: CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCN
Temperature: 50 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[2-(aminocarbonylmethyl)phenoxy]-2-methylpropionate (1.4 g, 4.87 mmol) was dissolved in tetrahydrofuran (5.0 mL). Subsequently, under nitrogen atmosphere, borane-THF complex in THF solution [1,0M BH3-THF in THF (14.6 mL, 14.6 mmol)] was added thereto, the mixture was stirred for three hours at 50° C. Thereafter, concentrated hydrochloric acid was gradually added thereto at 0° C. The resultant mixture was stirred for one hour at room temperature and made basic with an aqueous ethylamine solution. Ethyl acetate was added thereto. The mixture was sequentially washed with water and brine, followed by drying over sodium sulfate. The mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (830 mg, 2.97 mmol, 61%).