Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CCOC(C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:9])[N:6]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)CC1
Temperature: 120 °C

Procedure:
2-Amino-3,5-dibromopyrazine (1.26 g, 5.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.64 g, 25 mmol) were placed in a dry RBF and heated with stirring to 120° C. under dry nitrogen. Molten mixture was stirred at this temperature for 6 h and cooled to room temperature. The resulting slurry was diluted with EtOAc (20 mL) and stirred for 20 min. Amine salts were removed by filtration and washed with EtOAc (3×5 mL). Filtrate was washed with pH 4 buffer (35 mL) and brine (35 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 7:3) gives the title compound I-3r as an off white solid (1.64 g, 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:43])[CH2:34][C:35](=[O:42])[CH2:36][C:37]([O:39]CC)=O)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.FC1C=CC([C:51]2[N:52](CC[C@@H](O)CC(O)CC(OC)=O)[C:53](C(C)C)=C(C(=O)NC3C=CC=CC=3)C=2C2C=CC=CC=2)=CC=1>>[CH3:51][N:52]([CH3:53])[C:37](=[O:39])[CH2:36][CH:35]([OH:42])[CH2:34][C@H:33]([OH:43])[CH2:32][CH2:31][N:9]1[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(=O)CC(=O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Reactant: COC(=O)CC(O)C[C@H](O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)CC(O)CC(=O)N(C)C

Procedure:
In a process analogous to Step 6 METHOD A, using alternative Ru(II)-chiral diphosphine complexes in place of RuCl2(DMF)n[(R)—Cl—MeO-BIPHEP)] as the hydrogenation catalyst, one can obtain the identical products with varying enantiomeric excess at C-5. For example, in the reduction of 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, ethyl ester to (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, methyl ester proceeded as follows:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:28]#[N:29])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=3[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]21.[BH4-].[Na+]>O1CCCC1.CC(O)C.O>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=4[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([NH2:29])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 2.58 mL, 7.74 mmol) was added to a stirred solution of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (317 mg, 0.773 mmol) in tetrahydrofuran (7 mL) at 0° C. The resultant mixture was stirred at 60° C. for 1 hr. Ethylmagnesium bromide (3 M solution in diethyl ether, 2.58 mL, 7.74 mmol) was added to the reaction mixture at room temperature. The resultant mixture was stirred at 60° C. for 30 min. A suspension of sodium tetrahydroborate (585 mg, 15.5 mmol) in 2-propanol (7 mL) was added at room temperature. The resultant mixture was stirred at room temperature for 1 h, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a crude amorphous solid (392 mg).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:10][CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)cc1)OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 34 %

Procedure:
To triphenylpropanol (3.98 mmol), 4-hydroxyphenylacetic acid (3.98 mmol), and triphenylphosphine (4.39 mmol) in dry THF (20 mL) at 0° C. under a nitrogen atmosphere, was added DEAD (4.39 mmol) in dry THF (20 mL) over 15 minutes. The reaction was stirred at room temperature for 16h and then the THF was evaporated. The residue was chromatographed on silica gel using 15-30% EtOAc/hexanes. White solid, mp=136°-138° C. (ether), 34% yield. 1H NMR δ 7.15-7.27 (m, 15H), 7.10 (d, J=8.5 Hz, 2H), 6.77 (d, J=8.5 Hz, 2H), 4.90 (s, 1H), 3.90 (t, J=7.9 Hz, 2H), 3.47 (s, 2H), 2.93 (t, J=7.9 Hz, 2H). Anal. calcd. for C29H26O3 : C, 82.44; H, 6.20. Found: C, 82.29; H, 6.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:17])[C:4]=1[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19].C(N(CC)CC)C.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>C1COCC1.C(=O)([O-])O.[Na+]>[C:34]([O:37][CH2:38][C:39]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18]([C:4]2[N:5]([CH3:17])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8](=[O:16])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:19])[CH2:22][CH2:23]1)=[O:40])(=[O:36])[CH3:35]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)[nH]c1ccccc12
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)[nH]c1ccccc12
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 3-methoxy-1-methyl-4-oxo-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxamide (300 mg, 0.87 mmol) and triethylamine (88 mg, 0.87 mmol) in THF (30 mL) was added acetoxyacetyl chloride (119 mg, 0.87 mmol) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The obtained solid was washed with diethyl ether-hexane to give the title compound (221 mg, 56%) as a white solid.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO.[Ni]>[ClH:1].[CH3:14][O:13][C:11]([CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:12]
Reactant: COC(=O)CC[C@H]1CC[C@H](N)CC1
Reactant: O=Cc1ccccc1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H]1CC[C@H](NCc2ccccc2)CC1

Procedure:
8.0 g of methyl 3-(trans-4-aminocyclohexyl)propionatehydrochloride, 4.3 g of benzaldehyde and 5.0 ml of triethylamine in 150 ml of methanol are hydrogenated with 1.0 g of Raney nickel at 50° C. under a hydrogen pressure of 50 psi for 4 hours. After cooling, the mixture is suction filtered and the filtrate is evaporated down. The residue is divided between ethyl acetate and water, the aqueous phase is adjusted to pH 8-9 with sodium hydroxide solution and extracted with ethyl acetate. The combined ethyl acetate phases are washed with saturated saline solution, dried and evaporated down. The residue is suspended in diethylether and mixed with methanolic hydrochloric acid. The precipitate is suction filtered, washed with diethylether and dried.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]=2[N:8]=1.N1C=CC=CC=1.[NH2:30][OH:31].Cl>C(O)C.O>[CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[N:30][OH:31])[C:9]=2[N:8]=1
Reactant: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=NO)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A solution of 2-[4-methyl-2-(3-pyridyl)thiazol-5-yl]-6,7-dihydro-5H-quinolin-8-one (0.024 g, 0.067 mmol) was dissolved in ethanol (1 mL) and pyridine (0.054 mL, 0.053 g, 0.67 mmol) was added at ambient temperature. To this was added H2N—OH.HCl (0.0070 g, 0.10 mmol) and the resulting yellowish suspension was stirred at ambient temperature monitoring by LCMS. The reaction was complete after 2 hours. The reaction mixture was diluted with water and extracted ethyl acetate. The organic phase was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with a 5 to 10% MeOH: CH2Cl2, gradient gave 13 mg (58%) of the title compound as a yellow solid, and as a single isomer with mp=212-215° C.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-:10].[K+]>CC(C)=O.N#N>[C:1]([O:7][CH2:8][I:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [I-]
Reactant: CC(C)(C)C(=O)OCCl
Agent: N#N
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCI
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Chloromethyl pivalate (6 mL) was dissolved in dry acetone (500 mL) in an atmosphere of N2. To the mixture was added dry potassium iodide (15.33 g), and the mixture was stirred at room temperature for two days. After this time the mixture was filtered to yield a clear solution of iodomethyl pivalate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[CH3:29][I:30]>>[I-:30].[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:5]1([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3][N+:2]([CH3:29])([CH3:1])[CH2:7][CH2:6]1)[CH3:28]
Reactant: CI
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CC[N+](C)(C)CC2)cc1
Product: [I-]
Yield: 98 %

Procedure:
Ethyl 2-(1-methyl-4-(4-pentylphenylsulfonamido)piperidin-4-yl)acetate (100 mg, 0.244 mmol) was treated with MeI as described in Example 2a to yield crude title compound (133 mg, 98%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 2H, J=8.0 Hz), 7.33 (d, 2H, J=8.0 Hz), 6.05 (s, 1H), 3.98 (q, 2H, J=6.7), 3.79-3.70 (m, 2H), 3.65-3.60 (m, 5H), 3.40 (s, 3H), 2.69 (t, 2H, J=7.0 Hz), 2.54 (s, 2H), 2.49-2.43 (m, 4H), 1.67-1.61 (m, 2H), 1.38-1.32 (m, 4H), 1.17 (t, 3H, J=6.4 Hz), 0.91 (t, 3H, J=6.7 Hz); MS ESI 425.3 [M+H]+, calcd for [C22H36N2O4S+H]+ 425.60.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.[Cl:8][C:9]1[CH:10]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[F:15].N12CCN(CC1)CC2>C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([NH:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:17])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: Nc1cccnn1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1cccnn1)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of pyridazin-3-amine (5.0 g, 52.63 mmol) in anhydrous acetonitrile (250 mL) was added 3-chloro-4-fluorobenzenesulfonyl chloride (12.05 g, 52.63 mmol) followed by 1,4-diazabicyclo[2,2,2]octane (5.9 g, 52.63 mmol). The reaction was stirred at room temperature for 18 hours. A solid was observed which was collected by filtration and washed with acetonitrile. The filtrate was concentrated in vacuo and the resulting residue purified by silica gel column chromatography (0%-10% methanol in chloroform gradient elution) to afford the title compound (5.3 g, 35%)
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].[CH3:10][CH:11]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C(OC(OCC)C(C[C@@H](C)CCCC(C)C)C(OCC)OCC)C>C(Cl)Cl>[CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([O:6][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[CH:14][C:13]([CH2:12][CH:11]([CH3:10])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:18][N:17]=2)=[CH:24][CH:23]=1)=[O:5]
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Reactant: CC(C)CCCC(C)Cc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(OCC)C(C[C@@H](C)CCCC(C)C)C(OCC)OCC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](Cl)C(=O)Oc1ccc(-c2ncc(CC(C)CCCC(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8 g of (S,S)-3-methyl-2-chloropentanoic acid, 16 g of optically active p-[5--(2,6-dimethylheptyl)-pyrimidin-2-yl]phenol [obtainable by condensation, known from the literature, of (S)-1,1,3,3-tetraethoxy-2-(2,6-dimethylheptyl)-propane with 4-hydroxyphenylamidine hydrochloride], 11.6 g of N,N-dicyclohexylcarbodiimide, 0.6 g of 4-N,N-dimethylaminopyridine and 300 ml of methylene chloride is stirred overnight at room temperature. After the urea derivative which has precipitated has been filtered off, the filtrate is washed with dilute hydrochloric acid and H2O and the organic phase is worked up in the customary manner. p-[5-(2,6-Dimethylheptyl)-pyrimidin-2-yl]-phenyl (S,S)-3-methyl-2-chloropentanoate is obtained.
Reaction SMILES: [S:1](=[O:5])(=O)(O)[OH:2].CS[C@@H:8]1[CH2:16][N:15]2[C@@H:10]([CH2:11][C:12](=[O:17])[CH2:13][CH2:14]2)[CH2:9]1.OO.[C:20](=O)([O-])O.[Na+]>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:20][S:1]([C@@H:8]1[CH2:16][N:15]2[C@@H:10]([CH2:11][C:12](=[O:17])[CH2:13][CH2:14]2)[CH2:9]1)(=[O:5])=[O:2]
Reactant: O=C([O-])O
Reactant: CS[C@H]1C[C@@H]2CC(=O)CCN2C1
Reactant: O=S(=O)(O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)[C@H]1C[C@@H]2CC(=O)CCN2C1
Yield: 71 %

Procedure:
4.6 ml (9.23 mmol) of a 2N aqueous sulfuric acid solution and 3 ml of an aqueous solution of sodium tungstate dihydrate (101 mg, 0.31 mmol) were added to a solution of 1.14 g (6.15 mmol) of (2S,8aS)-2-methylthio-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one [obtained as described in Preparative Example 12′ above] in 15 ml of methanol, and 1.35 ml (12.3 mmol) of a 30% aqueous solution of hydrogen peroxide were then added dropwise at 55° C. to the resulting mixture. The mixture was then stirred for 1 hour at the same temperature, at the end of which time 30 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to it before extracting with methylene chloride. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on an alumina column using ethyl acetate as the eluant to afford 945 mg (yield: 71%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[H-].[Na+].[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.CS(C)=O>CN(C=O)C>[ClH:17].[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1)(=[O:4])=[O:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(S(N)(=O)=O)cc43)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
A solution of 5-aminosulphonyloxindole (283 mg, 1.3 mmol), (prepared as described for the starting material in Example 60), in DMF (3.5 ml) was added dropwise to a suspension of sodium hydride (53 mg, 1.3 mmol, prewashed with hexane) in DMF (1.5 ml). The mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 0.44 mmol), (prepared as described for the starting material in Example 5), in DMF (4 ml) was added. The mixture was stirred for 20 minutes at 65° C., DMSO (2 ml) was added and heating was continued for 1 hour at 65° C. The mixture was allowed to cool, the volatiles were removed by evaporation and the residue was partitioned between ether and water. The aqueous layer was adjusted to pH7.8 with 1M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water and ether, and dried under vacuum. The solid was dissolved in methanol/methylene chloride (1/1) and 2.2M ethereal hydrogen chloride (1 ml) was added. The mixture was stirred for 10 minutes at ambient temperature and the volatiles were removed by evaporation. The solid residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(5-aminosulphonyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (62 mg, 24%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28]OC(=O)C(C)(C)C)[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:42])(=[O:41])[CH2:39][OH:40].Cl.C(O)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28][O:40][CH2:39][C:38]([OH:42])=[O:41])[C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Reactant: O=C(O)CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)COCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 52.7 %

Procedure:
In 30 ml of ethyl acetate was dissolved 1 g of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)-amino]benzyl}-2,3-dioxopiperazine, and 1 g of glycolic acid and 0.02 ml of N hydrogen chloride-ethanol solution were added, after which the resulting mixture was subjected to reaction at room temperature for 3 hours with stirring. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 100 ml of methylene chloride. The methylene chloride layer was washed with 30 ml of water and then 30 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (Wakogel C-200, eluted with chloroformethanol), and recrystallized from ethyl acetate-diisopropyl ether, to obtain 0.5 g (52.8% yield) of 1-benzyl-4-{4-[N-carboxymethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 85° to 90° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([O-:15])=[O:14])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: O=C([O-])C1=Cc2ccccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2ccccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
Into a solution. of methyl 7-(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (650 mg) in THF/methanol (5/2.5 ml) was added at room temperature an aqueous solution (2.1 ml) of potassium carbonate (622 mg), and the resulting mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (379 mg) as colorless crystals.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][CH:45]2[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][CH:45]3[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC(F)(F)CC2)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 49 and making variation as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.04 g, 13%): 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=15.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 6.55 (d, J=14.4 Hz, 1H), 3.88 (d, J=9.0 Hz, 2H), 3.39 (s, 3H), 2.25-2.11 (m, 2H), 2.04-1.66 (m, 6H), 1.54-1.41 (m, 2H), 0.97-0.89 (m, 2H), 0.67-0.61 (m, 2H); MS (ES−) m/z: 404.1 (M−1).
Reaction SMILES: O[CH:2]1[O:8][CH2:7][C@@:6]2([CH3:12])[C:9]([CH3:11])([CH3:10])[C@:3]1([NH:13][C:14](=[O:16])[CH3:15])[CH2:4][CH2:5]2.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCl>[CH3:12][C@:6]12[C:9]([CH3:10])([CH3:11])[C@:3]([NH:13][C:14](=[O:16])[CH3:15])([CH2:4][CH2:5]1)[CH2:2][O:8][CH2:7]2
Reactant: CC(=O)N[C@@]12CC[C@@](C)(COC1O)C2(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N[C@@]12CC[C@@](C)(COC1)C2(C)C
Reaction time: 5 h

Procedure:
To a stirred solution of step 2 intermediate (0.2 g, 0.88 mmol) in dry dichloromethane (5 mL) under nitrogen atmosphere, was added Et3SiH (0.84 mL; 5.28 mmol) at 0° C. To this boron trifluoride etherate (0.33 mL, 2.6 mmol) was added dropwise over a period of 10 minutes. Stirring was continued for 5 hours at room temperature. After completion, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with dichloromethane. Organic layer was separated and dried over anhydrous Na2SO4. Dichloromethane layer was concentrated under reduced pressure to obtain 165 mg of title compound. 1H NMR (400 MHz, CDCl3) δ ppm: 0.78 (s, 3H), 0.89 (s, 3H), 1.1 (s, 3H), 1.60-1.64 (m, 1H), 1.72-1.78 (m, 2H), 1.85 (s, 3H), 2.60-2.67 (m, 1H), 3.06 (d, J=10.96 Hz, 1H), 3.67 (d, J=10.92 Hz, 1H), 3.78 (d, J=10.48 Hz, 1H), 3.92 (d, J=10.48 Hz, 1H) 5.16 (bs, 1H). m/z (M+1): 212.2.