Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C:13]([N:15]2[CH2:24][C:23]([F:26])([F:25])[C:22]3[CH:21]=[N:20][C:19]([NH:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[CH2:9]OC)=[CH:4][C:3]=1F.[Cl:35]C1C=CC([C@H](N)COC)=CC=1F.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.FC1(F)C2C=NC(NC3CCOCC3)=NC=2CNC1>O.C(Cl)Cl>[Cl:35][C:3]1[CH:4]=[C:5]([C@H:8]([NH:12][C:13]([N:15]2[CH2:24][C:23]([F:25])([F:26])[C:22]3[CH:21]=[N:20][C:19]([NH:27][CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[CH3:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC[C@@H](N)c1ccc(Cl)c(F)c1
Reactant: COC[C@@H](NC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: FC1(F)CNCc2nc(NC3CCOCC3)ncc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)—N-(1-(4-chloro-3-fluorophenyl)-2-methoxyethyl)-5,5-difluoro-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (I-51) To a solution of 197 (0.0854 g, 0.293 mmol) and DCM (5 mL) was added sequentially TEA (0.123 mL, 0.880 mmol) and CDI (0.0476 g, 0.293 mmol) and the solution was stirred at RT for 30 min. To the solution was added dropwise a solution of TEA (0.123 mL, 0.880 mmol), 208 (0.090 g, 0.293 mmol) and DCM (5 mL). The reaction was stirred for 18 h then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 2% MeOH/DCM to afford 0.060 g (40.9%) of I-51: MS m/z (APCI-pos) M+1=499.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5](=[O:17])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1>[I:42][CH2:2][CH:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5](=[O:17])[CH2:4]1
Reactant: COc1ccc(CN2CC(CO)CC2=O)cc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC(CI)CC2=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To alcohol 80 (12.9 g, 0.055 mol) in PhMe was added triphenylphosphine (20 g, 0.077 mol), imidazole (10.8 g, 0.16 mol), and iodine (19 g, 0.075 mol). The suspension was stirred at room temperature 5 hours. A saturated aqueous solution of sodium thiosulphate was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases washed with brine, dried (MgSO4) and concentrated. Flash chromatography (6:1 to 4:1 toluene/acetone) of the residue gave iodide 81 as an oil. 11.9 g, 63%. MS, m/z (relative intensity): 346 [M+H, 100%].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]1[C:19]2[CH:18]=[C:17]3[C:20]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]4[C:26]([C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:6].[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:5][CH3:6])[C:19]1[CH:18]=[C:17]3[C:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:21]4[C:26]([C:16]3=[CH:15][C:14]2=1)=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c4ccccc4n(CC)c3cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c4cc(C(C)=O)ccc4n(CC)c3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (80 mL) in which were dissolved 10-ethyl-12,12-dihexyl-10,12-dihydro-10-aza-indeno[2,1-b]fluorene (5.95 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. The dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:16]#[N:17]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:16]#[N:17]
Reactant: COc1ccc(C#N)cc1F
Reactant: OCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OCc1ccccc1Br
Temperature: 90 °C
Yield: 71.4 %

Procedure:
To a solution of 2-bromobenzyl alcohol (16.50 g, 88.2 mmol) in DMF (100 ml) was added sodium hydride (60% dispersion in mineral oil, 2.94 g, 73.5 mmol) and this was followed by 3-fluoro-4-methoxybenzonitrile (8.88 g, 58.8 mmol) and the resulting mixture was heated to 90° C. for 2 h under N2. After cooling, the mixture was partitioned between ether and H2O, the organic layer washed sequentially with 0.5 N HCl and saturated brine and then dried over MgSO4. Trituration with ether/pentane (1/3, v/v) afforded the subtitle compound as an off-white solid (13.35 g, 71%). Rf 0.27 (hexane/EtOAc 5/1, v/v). MS m/z 318, 320 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 82.4 %

Procedure:
Using 5-bromo-2-picolinic acid (5.0 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (4.7 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (7.6 g) was obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[N:19]1([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc2c(c1)CCN2
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccccc21
Yield: 67.9 %

Procedure:
The product is prepared by following the procedure described in example 1d, step 3d, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 238 mg of indoline instead of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride. 230 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink solid, the characteristics of which are the following:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][OH:10]>O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][C:9]([OH:2])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CC(C)CCCC(C)CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CCCC(C)CC(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of chromium trioxide (55.5 g, 0.555 mol) in water (68 ml) and 2M-sulphuric acid (12 ml) was added dropwise to a solution of 3,7-dimethyloctanol (43.7 g, 0.308 mol) in acetone (100 ml), the temperature was maintained at 40-60° C. and the reaction mixture was left stirring overnight. Acetone was carefully removed in vacuo, the reaction mixture was diluted in water and washed with diethyl ether (2×200 ml). The ethereal solution was washed with 10% sodium hydroxyde solution (200 ml); and the aqueous phase was acidified with 36% HCl (200 ml) and washed once more with diethyl ether (2×200 ml). The organic layer was dried (MgSO4) and the diethyl ether was removed in vacuo. The crude product was distilled to give a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[S-:12][C:13]#[N:14].[Na+].[Br-].[Na+].BrBr.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(Cl)(Cl)Cl.O>[CH3:1][O:2][CH2:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][C:10]=1[S:12][C:13]#[N:14])[NH2:7]
Reactant: N#C[S-]
Reactant: COCc1cccc(N)c1C
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COCc1c(SC#N)ccc(N)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
22.6 g (0.15 mol) of 3-methoxymethyl-2-methylaniline was dissolved in 300 ml of methanol. Then, 36.5 g of sodium thiocyanate was added thereto to obtain a uniform solution. This solution was cooled to 0° C., and 100 ml of a saturated methanol solution of sodium bromide with 25.2 g of bromine was dropwise added thereto so that the reaction temperature did not exceed 5° C. After the dropwise addition, the mixture was stirred at a temperature of not higher than 5° C. for 1 hour and at room temperature for 1 hour to complete the reaction. The reaction solution was poured into 1 liter of water and neutralized with a 5% sodium carbonate aqueous solution. Chloroform was added to extract the oily substance. The chloroform layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 29.6 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:12])[CH:3]=1.[C:13](=[NH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=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]>[C:20]1([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:26][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([F:12])[CH:3]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)cc2ncccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1cc(N=C(c2ccccc2)c2ccccc2)cc2ncccc12
Temperature: 110 °C

Procedure:
A mixture of 7-bromo-5-fluoroquinoline (128 mg, 0.566 mmol), benzophenone imine (0.143 mL, 0.849 mmol, Aldrich), Pd(dba)2 (32.6 mg, 0.057 mmol, Strem), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (70.5 mg, 0.113 mmol, Aldrich) and sodium 2-methylpropan-2-olate (82 mg, 0.849 mmol, Aldrich) in toluene (4 mL) was stirred at 110° C. for
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.Br[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([CH2:31][N:32]([CH:40]1[CH2:42][CH2:41]1)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:20][N:21]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30]>O1CCOCC1.O.Cl[Pd]Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:40]1([N:32]([CH2:31][C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[CH:25][C:17]=3[CH3:1])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:20]=2)[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:42][CH2:41]1
Reactant: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Br)cccc21
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Solvent: O
Product: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(C)cccc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 96.9 %

Procedure:
Potassium carbonate (207 mg), trimethylboroxin (175 μL) and bis(diphenylphosphino)ferrocene dichloropalladium (II) (40.8 mg) were added to a solution of tert-butyl {[4-bromo-1-(3-methoxypropyl)-1H-indol-3-yl]methyl}cyclopropylcarbamate (218 mg) in 1,4-dioxane (14.5 ml) and the mixture was stirred at 110° C. under argon atmosphere for 4 hours. After being cooled to room temperature, the reaction mixture was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=1/1 to 1/4) to give tert-butyl cyclopropyl{[1-(3-methoxypropyl)-4-methyl-1H-indol-3-yl]methyl}carbamate (180 mg) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:20][O:21][CH3:22])[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH2:31][C:32]([NH2:34])=[NH:33]>CN(C=O)C>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH2:31][C:32]1[NH:33][C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:20][O:21][CH3:22])[C:15]3[S:16][CH:17]=[CH:18][N:19]=3)(=[O:13])=[O:12])=[CH:7][CH:6]=2)=[CH:2][N:34]=1
Reactant: COCN(c1nccs1)S(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(-c2cnc(Cc3c(Cl)cccc3Cl)[nH]2)cc1
Temperature: 25 °C
Yield: 4.8 %

Procedure:
A solution of 4-(2-bromo-acetyl)-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (0.062 mmol) and the free base of 2-(2,6-dichloro-phenyl)-acetamidine (0.062 mmol) in DMF (2 mL) was heated to 80° C. for 2 h. After cooling to room temperature, the reaction mixture was purified by reverse phase chromatography to yield 4-[2-(2,6-dichloro-benzyl)-3H-imidazol-4-yl]-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (0.003 mmol).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>[Pd].C1COCC1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Reaction time: 4 h

Procedure:
To a 2-L PAAR hydrogenation bottle was charged Pd/C (10%, 11.06 g) and part of THF (1.11 L). Solid 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole (as prepared in the previous step, 221.1 g) was added along with the rest of the THF. The bottle was connected to the PAAR shaker, cycled through vacuum/nitrogen (3×), vacuum/hydrogen (3×) and the 45 psi hydrogen was applied with shaking Over the course of 4 hrs, the pressure dropped and was recharged until 45 psi was maintained. The reaction was complete by LCMS. The catalyst was filtered using celite/glass fiber filter, and the reaction was evaporated, but not to complete dryness. Denatured EtOH (250 mL) was added, the reaction concentrated, but again not to dryness. EtOH (1050 mL) was added, the contents heated to boiling, which dissolved nearly all the material. The mixture was allowed to come to ambient temperature with stirring and the product precipitated. After coming to ambient temperature, the suspension was chilled in a refrigerator for 3 hrs, and the product was filtered, and washed with ice-cold EtOH (250 mL) to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ: 7.79-8.04 (m, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=6.8 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 4.00 (s, 4H), 2.74-3.03 (m, 1H), 2.09 (br. s., 2H), 1.66-1.96 (m, 6H). 13C NMR (101 MHz, CHLOROFORM-d): 136.4, 126.8, 121.9, 119.3, 111.1, 108.9, 77.2, 64.3, 35.1, 34.1, 31.0.
Reaction SMILES: [C:1](Cl)(=O)[O:2]C(C)C.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[C:11]([OH:13])=[O:12].C(Cl)(=O)C>O1CCOCC1>[Cl:18][C:14]1[C:10]2[C:11](=[O:13])[O:12][C:1](=[O:2])[NH:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: C1COCCO1
Solvent: CC(=O)Cl
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 90 °C
Yield: 76 %

Procedure:
Under an atmosphere of nitrogen, isopropyl carbonochloridate (50 ml, 4.50 equiv) was added dropwise to a suspension of 2-amino-6-chlorobenzoic acid (20 g, 116.56 mmol, 1.00 equiv) in 1,4-dioxane (150 ml). The resulting solution was maintained at about 90° C. for 30 minutes, and then cooled to about 50° C. Acetyl chloride (50 ml, 6.00 equiv) was added in one portion, and the solution was maintained at about 50° C. for about 30 minutes. The resulting solids were collected by filtration and purified by silica gel chromatography (ethyl acetate/petroleum ether 10:1) to afford the title product as a gray white solid (17.6 g, yield: 76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33].[I-].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=2[C:32]([F:34])([F:33])[F:35])[C:7]=1[CH3:16])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of (5-fluoro-2-methyl-1H-indol-3-yl)-acetic acid ethyl ester (100 mg, 0.43 mmol) in dry DMSO (2 ml) at room temperature, is added sodium hydride (26 mg, 0.65 mmol) as a 60% dispersion in mineral oil. After stirring at room temperature for 30 mins, 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (216 mg, 0.68 mmol) (intermediate 1c) and sodium iodide (102 mg, 0.68 mmol) are added. The reaction mixture is stirred at room temperature for 60 h. The reaction mixture is poured into water (20 ml) and extracted with EtOAc (20 ml). The organic phase is dried (MgSO4) and evaporated to dryness in vacuo. The crude product is purified by reverse phase chromatography on a C18 Isolute™ cartridge, eluting in 0-100% MeCN in water, using a FlashMaster Personal™ and GradMaster™; [M+H]+ 472.
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12](CC)[N:13]=2)[N:10]=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:8][C:9]3[N:10]([CH3:5])[N:13]=[N:12][N:11]=3)[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(NC(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 5-(chloromethyl)-1-methyl-1H-tetrazole. MS (m/e): 394.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([N:16]([CH3:18])[CH3:17])C#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH:39]1([CH:45]=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[Cl-].[NH4+].C#N.C(O)(=O)C(O)=O>O1CCCC1.CCCCCC.CO>[CH:39]1([C:45](=[O:46])[CH:13]([C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:12][CH2:11][CH2:10]2)[N:16]([CH3:18])[CH3:17])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=CC1CCCCC1
Reactant: CN(C)C(C#N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: C#N
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)C(=O)O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CO
Product: CN(C)C(C(=O)C1CCCCC1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 3 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-dimethylaminoacetonitrile (11.3 g prepared as described in Example A(c)) in tetrahydrofuran (20 ml) was added over a period of ten minutes to a solution of lithium diisopropylamide at -50° C. [prepared by the addition of a 2.7M solution of butyllithium in hexane (24.7 ml) to a solution of diisopropylamine (10.25 ml) in dry tetrahydrofuran (30 ml) at 10°-15° C. under argon] and the mixture was allowed to warm to 3° C. and maintained at 3° C. for 30 minutes. The mixture was cooled to -70° C. and cyclohexanecarbaldehyde (11.5 g) was added with stirring over a period of 20 minutes. Stirring was continued at this temperature for a further 40 minutes and then saturated aqueous ammonium chloride solution (100 ml) was added slowly at -70° C. The mixture was allowed to warm to 20°-25° C. and the aqueous layer was separated and extracted with ether. The ether extracts were combined with the organic layer of the reaction mixture, dried and evaporated to give an oil which was heated (eliminating hydrogen cyanide) at 90°-95° C. for 3 hours and then cooled and dissolved in methanol (100 ml). Oxalic acid (10 g) was added and the mixture heated at 90°-95° C. for one hour. The mixture was cooled, basified and extracted with ether. The ether extract was dried and evaporated to give an oil which was purified by flash chromatography using a 95:5 mixture of petroleum ether and ether as eluant. The resulting oil solidified on standing and was recrystallised from petroleum ether (b.p. 60°-80° C.) to give 1-cyclohexyl-2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-dimethylaminoethanone (m.p. 79°-80° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:19]([OH:21])=O)[N:8]=[C:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][CH:3]=1.[CH2:22]([N:24](CC)[CH2:25][CH3:26])[CH3:23].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:19]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:21])[CH3:23]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccc(Cl)cc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccc(Cl)cc2c(-c2ccccc2Cl)n1
Yield: 59 %

Procedure:
Operations are carried out as for Example 7, starting from 3.18 g of 7-chloro 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.16 g of triethylamine, 1.25 g of ethyl chloroformate and 0.95 g of diethylamine in 100 ml of chloroform. 2.2 g of N,N-diethyl 7-chloro 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 145° C., are obtained.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>CN(C=O)C>[CH3:5][C:4]([CH3:6])=[CH:3][CH2:2][N:11]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:12]
Reactant: CC(C)=CCBr
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: CC(C)=CCN1C(=O)c2ccccc2C1=O
Yield: 63.4 %

Procedure:
20 g of 1-bromo-3-methylbut-2-ene and 26.1 g of phthalimide are suspended in anhydrous DMF, and then the mixture is refluxed for 12 h with heating. After returning to RT, the reaction medium is filtered and then taken up with an aqueous solution saturated with NH4Cl. The aqueous phase is extracted with AcOEt, washed with a solution of NaCl, and then dried on magnesium sulfate and dry evaporated. The obtained solid is suspended in 100 mL of water and stirred. The precipitated product is filtered, rinsed with ether and then dried in the oven in vacuo at 65° C. 18.3 g (yield=63%) of 2-(3-methylbut-2-en-1-yl)-1H-isoindole-1,3-dione are obtained as a white powder used as such.