Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH:13]=[CH2:14])[CH:5]([OH:11])[CH2:6][C:7]([O:9]C)=[O:8])[CH2:2][CH3:3]>[OH-].[K+].CO>[CH2:12]([CH:4]([CH2:1][CH:2]=[CH2:3])[CH:5]([OH:11])[CH2:6][C:7]([OH:9])=[O:8])[CH2:13][CH3:14]
Reactant: C=CCC(CCC)C(O)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(CCC)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-propyl-3-hydroxyhept-6-enoate (3.24 g, 16.2 mmol) was dissolved in a 2 N potassium hydroxide-methanol solution (16 mL), and the solution was stirred overnight at room temperature. From the reaction solution, the solvent was distilled off under reduced pressure. To the residue, a 1 N aqueous sodium hydroxide solution (150 mL) was then added, followed by extraction with diethyl ether. The aqueous layer was made acidic by the addition of concentrated hydrochloric acid under ice cooling, followed by extraction with diethyl ether again. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (2.79 g, 92%, mixture of diastereomers).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:7]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][NH2:24])=O)=[CH:16][CH:15]=1>C(O)CCC>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=3)=[N:23][N:24]=2)[N:4]=1
Reactant: NNC(=O)Cc1ccc(O)cc1
Reactant: Clc1ccc(-c2cccs2)nn1
Solvent: CCCCO
Product: Oc1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1
Temperature: 25 °C

Procedure:
A solution containing 3-Chloro-6-thiophene-2-yl-pyridazine (58 mg, 0.29 mmol) Example 17: step a and (4-Hydroxy-phenyl)-acetic acid hydrazide (120 mg, 0.58 mmol) in butanol (5 mL) was heated to reflux overnight. The reaction was cooled to rt and the solids were filtered and washed with MeOH. The solid was recrystallized from MeOH to yield the title compound as a tan solid. 1H-NMR (CD3OD/CDCl3): δ 8.12-8.10 (1H, d, J=9.34 Hz), 7.83-7.82 (1H, d, J=3.7 Hz), 7.78-7.76 (1H, d, J=9.8 Hz), 7.67-7.65 (1H, d, J=5.0 Hz), 7.34-7.32 (2H, d, J=6.5 Hz), 7.22-7.21 (1H, m), 6.77-6.75 (2H, d, J=8.3 Hz), 4.49 (2H, s). ESI-MS (m/z): Calcd. For C16H12N4OS: 308.07; found: 309.2 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].CC(C)([O-])C.[K+]>C(#N)C>[F:18][C:19]([F:23])([F:22])[CH2:20][O:21][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S1(=O)c2ccccc2Oc2cc(OCC(F)(F)F)ccc21
Yield: 77510.2 %

Procedure:
3-Fluorophenoxathiin 10,10-dioxide (Example 47) (6.27 g, 0.025 mmol) was added to a stirred solution prepared from 1,1,1-trifluoro-2-ethanol (Aldrich) (2.64 g, 0.0264 mole), potassium tert-butoxide (Janssen) (2.96 g, 0.0264 mole) and dry acetonitrile (170 mL). The mixture was heated at reflux under nitrogen for 1 hour. The reaction was cooled, and the volatiles were removed by spin evaporation in vacuo. The residue was partitioned between dichloromethane (200 mL) and water (100 mL). The layers were separated, and the organic phase was washed with 0.1 N aqueous hydrogen chloride (75 mL), brine (75 mL) and then dried over magnesium sulfate. The dry solution was spin evaporated in vacuo to give a fluffy residue, which was recrystallized from ethanol to give 6.40 g (77% yield) of 3-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide, m.p. 167-168° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[CH:16][C:15]([NH:22][C:23](=[O:25])[CH3:24])=[CH:14][CH:13]=4)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br>C(Cl)Cl>[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:21])[C:19]=2[OH:20])=[CH:16][C:15]([NH:22][C:23](=[O:25])[CH3:24])=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: CC(=O)Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)Nc1ccc2oc(-c3ccc(O)c(O)c3)c(O)c(=O)c2c1
Yield: 93215920 %

Procedure:
20 mg (59pmol) of the compound obtained in Example 23 was dissolved in 2 ml of methylenechloride, and the mixture was reacted with excess amount of boron tribromide (BBr3) at room temperature for 3 hours. The resulting product was concentrated. Then the produced solid was washed with methylenechloride and 10% methanol/methylenechloride, filtered, and dried to give 18 mg of the title compound in a yield of 93%.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][C:17](=[O:21])[NH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10].CI.O>CN(C=O)C.CCOC(C)=O>[CH3:7][O:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:1])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: COC(=O)c1cccc2c1OCC(=O)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1OCC(=O)N2C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
K2CO3 (6.66 mmol) is added to a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid methyl ester (2.90 mmol) in DMF (10 mL). After 30 min methyl iodide (5.79 mmol) is added and the mixture is stirred for 2 h at 75° C. Cold water and EtOAc are added, the layers are separated and the aq. layer is extracted with EtOAc. The combined organic layers are washed with water and brine, dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.76 min; [M+H]+=222.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]I.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>CCOCC>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:22])=[CH:15][CH:16]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: C[Mg]I
Solvent: CCOCC
Product: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1

Procedure:
30 ml of ether solution containing 4.0 g of indole were added to 10 ml of ether solution containing 5.0 g of methylmagnesium iodide. And then 30 ml of ether solution containing 5.7 g of anisoyl chloride were added dropwise to the solution. The reaction mixture was allowed to stand for several hours and further refluxed for 3 hours. After cooling, the reaction mixture was washed with aqueous solution of sodium hydrogencarbonate. The obtained organic layer was evaporated to dryness under reduced pressure. After purification by chromatography on silica gel and recrystallization from ethanol, 3-(p-methoxybenzoyl)indole (compound 1) was obtained in the form of white crystals. (Yield: 42%)
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[CH:23]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1.CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>ClCCl>[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:18][C:17]=4[CH:23]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: C=CCOC(=O)Cl
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N1CCOc2ccc(-c3ccc4nc(C)[nH]c4c3)cc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-(2-methyl-1H-benzimidazol-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine dihydrochloride (6.95 g, 19.73 mmol) was suspended in dichloromethane (100 mL) and cooled to 0° C. To the resulting mixture was added DIPEA (19 mL, 109 mmol) followed by allyl chloroformate (4.6 mL, 43.4 mmol) and stirring was continued at 0° C. for 30 minutes then warmed to room temperature. The reaction mixture was then charged with additional DIPEA (3.4 mL) and allyl chloroformate (1 mL) then stirred an additional 30 minutes at room temperature. The resulting solution was then concentrated and the residue azeotroped once from methanol (100 mL). The residue was then taken back into methanol (100 mL) followed by portionwise addition of 2 M aqueous sodium hydroxide (20 mL) and the mixture was allowed to stir for 1 h at room temperature. The solution was then concentrated and the residue partitioned with chloroform and dilute brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give prop-2-en-1-yl 7-(2-methyl-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate as an amorphous residue which was carried forward directly into step 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)([CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:8]1=[O:33].[F-].[NH4+]>>[CH3:40][O:39][C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:36]=1[O:37][CH3:38])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)([CH2:12][CH2:13][OH:14])[C:8]1=[O:33]
Reactant: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)(Cc3ccc(C(F)(F)F)cc3)C2=O)cc(OC)c1OC
Agent: [F-]
Agent: [NH4+]
Product: COc1cc(CN2CCC(CCO)(Cc3ccc(C(F)(F)F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 17.4 using 1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (0.6 g, 1.0 mmol) and ammonium fluoride (0.23 g, 6.2 mmol) to give the title compound: Rf=0.35 (silica gel, ethyl acetate).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[O:16])=[CH:10][CH:9]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: c1ccoc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)c2ccco2)cc1
Yield: 35.2 %

Procedure:
Furan (5 g, 73.5 mmol) in CH2Cl2 (10 ml) was added to a solution of p-methoxyphenylacetyl chloride (2.21 g, 14.7 mmol) and trifluoromethanesulfonic acid (150 μl) in CH2Cl2 (25 ml) at reflux. The reaction was quenched after 3 hours by pouring the solution over a 10% HCl/ice slurry. The organic layer was washed with 10% aqueous NaOH, dried over MgSO4, and the solvent was removed under reduced pressure. The crude oil was chromatographed ion SiO2 (85 g), eluting with Hexane/EtOAc, 4/1, to give 20 (1.12 g, 35.3%) 41.5°-43.0° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1.Cl.[CH2:15]([O:17][C:18](=[O:28])[CH2:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:28])[CH2:19][C@@H:20]([NH:27][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:16]
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1cnc(C2CC2)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](Nc1nc(C2CC2)ncc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Chloro-2-cyclopropyl-5-nitro-pyrimidine (597 mg, 3 mmol) in DMF (10 ml) was added (R)-3-Amino-3-phenyl-propionic acid ethyl ester hydro chloride (582 mg, 3 mmol). The mixture was stirred on ice for 5 minutes the DIPEA (580 mg, 4.5 mmol) was added. The solution was stirred at room temperature for one hour. TLC showed disappearance of the starting material. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, evaporated to dryness to give oil, which was used as such for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[O:5][CH2:6][CH2:7][NH2:8].[CH3:16][C:17]1C=CC(S(OCCC)(=O)=O)=C[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:8][CH2:16][CH2:17][CH3:18]
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C
Yield: 43.2 %

Procedure:
2-[3-Fluoro-5-(methylsulfonyl)phenoxy]ethanamine (0.3 g, 1.26 mmol), propyl 4-methylbenzenesulfonate D2 (1.04 ml, 12.76 mmol) and potassium carbonate (0.35 g, 2.52 mmol) in acetonitrile (10 ml). The mixture was heated under microwave radiation at 120° C. for 45 min. The reaction mixtures were cooled to room temperature, filtrated and pooled before the volatiles were evaporated. Purification by flash column chromatography (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.15 g, 44%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether. MS m/z (relative intensity, 70 eV) 277 (M+, 2), 248 (26), 138 (3), 94 (3), 74 (bp).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[Br:15][C:16]1[CH:17]=[C:18]2[C:29](=[CH:30][CH:31]=1)[O:28][C:21]1[C:22]([F:27])=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[N:32]S(C(C)(C)C)=O>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]3([C:11]4[C:8](=[CH:7][CH:14]=[CH:13][CH:12]=4)[C:9]([NH2:10])=[N:32]3)[C:20]3[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([F:27])[C:21]=3[O:28][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: N#Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2ccccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 0.75 mL, 1.2 mmol, Aldrich) was added dropwise to a solution of 2-bromobenzonitrile (219 mg, 1.2 mmol, Oakwood Products) in THF (30 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was allowed to stir for 5 min at −78° C. Subsequently, a solution of N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (400 mg, 0.93 mmol, step 1) in THF (30 mL) was added. After 5 min, the reaction mixture was quenched with aqueous, saturated solution of NH4Cl and EtOAc was added. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (55-100% EtOAc/hexanes) to afford the title compound as a yellow solid. MS m/z=431.9 [M+H]+. Calculated for C19H10BrClFN3O: 430.7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1)(=[O:10])=[O:9].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>ClCCCl>[CH3:18][C:16]1[CH:17]=[C:12]([N:11]2[C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:13]=[N:14][C:15]=1[CH3:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(NS(=O)(=O)c2ccccc2N)cnc1C
Solvent: ClCCCl
Product: Cc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cnc1C
Yield: 55 %

Procedure:
The title compound (2.17 g, 7.15 mmol) was prepared from 2-amino-N-(5,6-dimethylpyridin-3-yl)benzenesulfonamide (2.7 g, 13.0 mmol) and 1,1′-carbonyldiimidazole (4.74 g, 29.2 mmol) in 1,2-dichloroethane (25 mL) at 110° C. for 3 h using the methods of (IntA14), step 3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([OH:3])=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=C(C)C=C(C)C=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[C:11](=[O:13])[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:3])=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1Cc2ccccc2C(=O)N1c1ccc(Cl)cc1

Procedure:
2-(2-Carboxyphenyl)acetic acid (9 g) and 4-chloroaniline (6.3 g) in mesitylene (200 ml) were heated at reflux for 18 h, under Dean and Stark conditions. On cooling, the crude product crystallised out and was filtered off. Recrystallisation from ethanol/ethyl acetate gave 2-(4-chlorophenyl)isoquinoline-1,3(2H,4H)-dione, m.p. 178°-180° C. A mixture of this product (2.8 g) and phosphoryl chloride (10 ml) was heated at reflux for 21 h, and excess phosphoryl chloride was then evaporated at reduced pressure. The residue was stirred in ice-water for 4 h, and the precipitate filtered off and suspended in 2% aqueous sodium bicarbonate for 5 minutes. It was again filtered off, taken up in dichloromethane (150 ml) dried and evaporated. Column chromatography of the residue gave a brown solid, which was recrystallised from isooctane/ethyl acetate, to give 3-chloro-2-(4-chlorophenyl)isoquinolin-1(2H)-one m.p. 125°-127° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2ccc(F)c(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 82 (0.4 g, 0.71 mmol), was reacted with diisopropylethylamine (0.82 g, 6.4 mmol), diphenylphosphinic chloride (0.67 g, 2.8 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.34 g, 2.8 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white foam (Yield, 0.18 g, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.[F-].[Cs+]>C(PC(C)(C)C)(C)(C)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Agent: [Pd]
Agent: CC(C)(C)PC(C)(C)C
Agent: [Cs+]
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ncccn3)s2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A round bottom flask containing 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), 2-tributylstannanyl-pyrimidine (130 mg, 0.36 mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium di-tert-butylphosphine was degassed three times with Ar. Dioxane was added and the formed reaction mixture was stirred at 90° C. overnight under Ar. Then the reaction mixture was filter through celite and the solvent was removed under vacuum and crude product was used directly in the next step.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][N:15]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[CH:16]1.CC1C=C(C2N(C)C=CN=2)C2C(=C(O)C=CC=2)N=1>>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[C:16]1[N:15]([CH3:14])[C:19]([C:20]#[N:21])=[CH:18][N:17]=1
Reactant: Cn1cncc1C#N
Reactant: Cc1cc(Br)c2cccc(O)c2n1
Agent: Cc1cc(-c2nccn2C)c2cccc(O)c2n1
Product: Cc1cc(-c2ncc(C#N)n2C)c2cccc(O)c2n1

Procedure:
Coupling of 4-bromo-2-methyl-quinolin-8-ol (400 mg. 1.68 mmol) with 3-methyl-3H-imidazole-4-carbonitrile (450 mg. 4.20 mmol) according to the synthesis of 2-methyl-4-(1-methyl-1H-imidazol-2-yl)-quinolin-8-ol yielded the title compound. MS (m/z): 265.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]
Reactant: O=C1CCCC1Cl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
23.8 g of methyl 3-hydroxy-4-methoxybenzoate are dissolved in 200 ml of anhydrous DMF and the solution is treated with 35 g of potassium carbonate (ground) and 13 ml of 2-chlorocyclopentanone. The mixture is stirred at 60° C. for 3 h, then the solid is filtered off with suction and the filtrate is concentrated in vacuo. The residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 24.3 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=[C:2]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:33][N:32]=2)(=[O:36])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1Cl
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Yield: 96.4 %

Procedure:
A solution of 1.18 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine and 2.12 g (8.88 mmol) of 5-isopropyl-pyridine-2-sulphonamide potassium salt in 25 ml of dry DMSO was heated to 80° C. for 3 hours until the dichloride had disappeared completely. The DMSO was removed in a high vacuum, the residue was taken up with 60 ml of water and the aqueous solution was washed three times with diethyl ether. The solution was then acidified to pH 3.5 with 1N HCl and the product was extracted three times with ethyl acetate. The organic phases were washed twice with water and finally once with saturated sodium chloride solution, combined, dried with sodium sulphate and evaporated. The crystalline residue was digested twice with absolute diethyl ether in order to completely remove a trace of 5-isopropyl-pyridine-2-sulphonamide. The crystals remaining behind were filtered off and dried. There were obtained 1.66 g (96%) of 5-isopropyl-pyridine-2-sulphonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide as white crystals of m.p. 168°-176° C., MS: (M-H)- =518.3.