Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[C:33](=[CH:20][C:17]1[NH:16][C:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:2]4([OH:1])[CH2:3][CH2:4][N:5]([CH3:8])[CH2:6][CH2:7]4)[C:11](=[O:22])[C:12]=3[C:18]=1[CH3:19])[C:34](=[O:40])[NH:35]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 74.98 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (67 mg, 74.98%) as an orange solid.
Reaction SMILES: C[C:2]1([CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][CH:6]1[N+:14]([O-:16])=[O:15])[C:3]([O-])=[O:4].CCOCC.CO.[Li+].[BH4-]>C1COCC1>[OH:4][CH2:3][C:2]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1(C(=O)[O-])C=CC(C(=O)[O-])=CC1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a suspension of 1-methyl-2-nitroterephthalate (10.2 g, 45.1 mmol) and 150 mL of anhydrous ether was added 5.2 mL of anhydrous MeOH at which point most of the solid went into solution. The solution was cooled to 0° C. and LiBH4 (in THF, 57.0 mL, 114.0 mmol, Aldrich) was added slowly over 50 min. Bubbles were generated. The resulting mixture was stirred at RT for 5 h, then heated to 35° C. TLC showed ˜20% conversion. 100 mL of anhydrous THF was added and the reaction was heated to 55° C. After 3 days, TLC showed reactions to be complete. The reaction was carefully quenched with the addition of H2O, and neutralized with 1N HCl. The organic layer was separated and the aqueous layer was extracted with ether (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a light yellow solid. MS m/z: 196.1 (M−1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[O:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=1.[CH3:16][Mg]Cl.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CC(OC)(C)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[O:13][C:12]([CH:14]([OH:15])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1ccc(COC2CCCCO2)o1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(COC2CCCCO2)o1
Temperature: 1 °C
Reaction time: 1 h

Procedure:
Crude 5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-carbaldehyde (171 g) was dissolved in THF (1 L) and cooled to 1° C. Methylmagnesium chloride (3 M in THF, 325 mL, 0.97 mol) was then added while keeping the internal temperature below 5° C. After the addition, the reaction mixture was stirred at rt for 1 h. Water (1 L), TBME (1 L) and 40% aq. citric acid (200 mL) were added, the layers separated and the org. layer washed with water (500 mL) and evaporated to dryness to give crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanol. Part of the crude material (96 g, 0.43 mol) was dissolved in CH2Cl2 (1 L) and treated with MnO2 (371 g, 4.26 mol) at rt. The reaction mixture was heated to 45° C. and stirred at this temperature for 24 h. The mixture was then filtered over celite and the filter cake washed with CH2Cl2. The filtrate was evaporated to dryness to give crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanone as a yellow oil.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20]N.Cl>C(O)C>[C:1]([NH:4][CH:5]1[CH2:10][C:9]2[C:16]3[C:15](=[C:14]([F:13])[CH:19]=[CH:18][CH:17]=3)[NH:20][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:1]([NH:4][CH:5]1[CH2:10][C:9]2[C:16]3[C:15](=[C:14]([F:13])[CH:19]=[CH:18][CH:17]=3)[NH:20][C:8]=2[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CCO
Product: CC(=O)NC1CCc2[nH]c3c(F)cccc3c2C1
Product: CCNC1CCc2[nH]c3c(F)cccc3c2C1

Procedure:
A solution of 7.8 g. of 4-acetamidocyclohexanone and 8.1 g. of 2-fluorophenylhydrazine hydrochloride in 75 ml. of absolute ethyl alcohol and 25 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and adsorbed on a column of aluminum oxide. Dilution with ether yielded first a small amount of side-product followed by the desired product which was recrystallized by dissolving in methyl alcohol, adding toluene, and evaporation of the methyl alcohol, to give 10.5 g. of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 202°-204° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[CH2:20]Br.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[CH2:20][S:11]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:37]3[CH2:36][CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:39][CH2:38]3)[C:7]=2[CH:8]=1)(=[O:13])=[O:12]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Li+]
Solvent: CC#N
Product: COc1cc(CS(=O)(=O)c2cc3c(N4CCN(C(=O)OC(C)(C)C)CC4)nccc3s2)cc(OC)c1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3,5-dimethoxybenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.02 g (10% over two steps). Beige solid. 1H NMR (300 MHz, CDCl3) δ 8.14-8.18 (m, 1H), 7.55 (s, 1H), 6.40-6.45 (m, 1H), 6.26-6.34 (m, 2H), 4.39 (s, 2H), 3.54-3.72 (m, 14H), 1.50 (s, 9H); MS (ESI+) for C25H31N3O6S2 m/z 534 (M+H)+. HPLC 69%, RT 1.99 min (YMC ODS AQ, 33×3 mm, 10-90% acetonitrile in 3 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1[C:8]([F:18])=[N:9][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:6]=1[C:5]2=O.[CH3:24][Si](C[Li])(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1[C:8]([F:18])=[N:9][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:6]=1[C:5]2=[CH2:24]
Reactant: CC(C)(C)COc1cc2c(=O)c3cc(Br)ccc3oc2c(F)n1
Reactant: [Li]C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C=C1c2cc(Br)ccc2Oc2c1cc(OCC(C)(C)C)nc2F
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a suspension of 7-bromo-1-fluoro-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridin-5-one (1000 mg, 2.63 mmol) in THF (25 mL) at −40° C. was added drop wise ((trimethylsilyl)methyl)lithium (1.0M solution in pentane; 3.95 mL, 3.95 mmol). After 10 min, TFA (0.304 mL, 3.95 mmol) was added drop wise and the reaction mixture was allowed to warm to rt Additional 1 ml of TFA was added and the reaction mixture was allowed to stir for 1 hour at P. An aqueous, saturated K2CO3 solution was added, followed by EtOAc. The organic phase was separated and dried over Na2SO4. The solvent was removed under reduced pressure to yield 7-bromo-1-fluoro-5-methylene-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridine as a yellow solid (995 mg), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCCCC(N)c1cc(Br)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCCC(NC(C)=O)c1cc(Br)ccn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.0 g of 1-(4-bromopyridin-2-yl)-4-methoxybutylamine in 150 ml of glacial acetic acid is mixed with 37 ml of acetic anhydride. The reaction solution is stirred at 50° C. for 30 minutes and then diluted with ethyl acetate. It is basified with 2M sodium hydroxide solution, and the phases are separated. The aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are evaporated. The title compound is obtained as a yellowish solid from the residue by flash chromatography (SiO2 60 F). Rf=0.38 (EtOAc-methanol 9:1); Rt=2.33 (Gradient I).
Reaction SMILES: [CH3:1][C:2]1[C@@H:3]2[C@@H:19]([C@:20]3([CH3:28])[C:25]([CH:26]=1)=[CH:24][C:23](=[O:27])[CH2:22][CH2:21]3)[CH2:18][CH2:17][C@@:16]1([CH3:29])[C@H:4]2[CH2:5][CH2:6][C@@H:7]1[C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C1CCCCC=1.N#N>[Pd].C(O)C>[CH3:1][C@H:2]1[CH2:26][C:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C:23](=[O:27])[CH:24]=2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: N#N
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of methyl 7-methyl-3-oxochola-4,6-dien-24-oate (9) (0.62 g, 1.56 mmoles), 5% palladium on carbon (72 mg), 1,8diazobicyclo-[5.4.0]undec-7-ene (15 gl), cyclohexene (4.9 ml) and ethanol (3.6 ml) was heated under reflux in an N2 for 6 hrs. The cooled mixture was filtered, and the catalyst washed with ethanol (4 times). The combined filtrate and washes were evaporated in vacuo. The residue was dissolved in EtOAc (30 ml), washed with 0.5M HCl, H2O, saturated brine and dried (MgSO4). Evaporation in vacuo gave 0.62 g of pure 10 as a pale yellow syrup. NMR (CDCl3): δ0.71 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.05 (d, 3H, 7-Me); 1.15 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 5.70 (s, 1H, 4-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][C:27]=4[O:36][CH3:37])=[O:24])[NH:12][C@H:11]3[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:5]2=[CH:4][CH:3]=1.CC[N:46]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[C:33]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23]([C@@H:13]2[NH:12][C@@H:11]([CH2:38][C:39]([CH3:42])([CH3:40])[CH3:41])[C@:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:43])[C@H:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[C:27]([O:36][CH3:37])[CH:28]=1)(=[O:34])[NH2:46]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 80 °C

Procedure:
To a solution of chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-phenyl)-acetic acid (0.1 g, 0.17 mmol) prepared in Example 160 in anhydrous DMF (2 mL) were added EDCI (64 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), NH4Cl (89 mg, 1.67 mmol), and triethylamine (34 mg, 0.33 mmol) sequentially. The reaction mixture was heated at 80° C. for 3 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoylmethyl-2-methoxy-phenyl)-amide as a off white solid (81 mg, 77%).
Reaction SMILES: C[Si](C)(C)O[C:4]1[CH:20]=[CH:19][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.OC1C=[CH:39][C:27]([C:28]([O:30]C2C=CC(CC)=CC=2)=[O:29])=[CH:26]C=1.C(OC(=O)C(C)=C)(=O)C(C)=C.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1.C(O)C>[C:28]([O:30][C:19]1[CH:20]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)=[O:9])(=[O:29])[C:27]([CH3:39])=[CH2:26]
Reactant: CCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Reactant: CCc1ccc(OC(=O)c2ccc(O[Si](C)(C)C)cc2)cc1
Agent: C=C(C)C(=O)OC(=O)C(=C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=C(C)C(=O)Oc1ccccc1C(=O)Oc1ccc(CC)cc1
Temperature: 100 °C

Procedure:
A solution of 16.9 g of 4-ethylphenyl 4-trimethylsilyloxybenzoate (prepared by the procedure in EP-A-358,208, page 9, sec. C) in 15 ml of toluene and 10 ml of ethanol was refluxed for 1 hour and then freed from volatile components by heating at 100° C. for 60 minutes. The remaining 13.3 g of 4-ethylphenyl 4-hydroxybenzoate were dissolved in 15 ml of toluene together with 30 g of methacrylic anhydride and 1.2 g of toluenesulfonic acid, and the mixture was heated at 100° C. for 1 hour. After cooling, the product was precipitated with hexane and recrystallized from ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:14]=[C:15]1[CH:19]([CH2:20]OS(C)(=O)=O)[CH2:18][CH2:17][N:16]1[C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]([F:46])([F:45])[F:44])[NH:32][C:33]2=[O:36])=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[N:1]1([CH2:20][CH:19]2[CH2:18][CH2:17][N:16]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:46])([F:45])[F:44])[NH:32][C:33]4=[O:36])=[CH:28][CH:27]=3)[C:15]2=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C(CN2CCOCC2)CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 21.9 %

Procedure:
Morpholine (0.024 ml, 0.29 mmol) and triethylamine (0.040 ml, 0.29 mmol) were added to a THF solution (1 ml) that contained the obtained methanesulfonic acid 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-pyrrolidin-3-ylmethyl ester (14 mg, 0.029 mmol). The obtained mixture was heated to reflux for 16 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1->30:1), so as to obtain 7-(3-morpholin-4-ylmethyl-2-oxo-pyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (3 mg, 22%) in the form of a colorless oil substance.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH3:16][S:17](Cl)(=[O:19])=[O:18].[CH3:21]O>>[CH3:16][S:17]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:21])=[O:8])=[CH:10][CH:11]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(aminomethyl)benzoic acid (10 g, 66 mmol) in MeOH (100 mL) at 0° C. was added SOCl2 (5.3 mL, 73 mmol) dropwise. The ice bath was removed and the reaction stirred at rt overnight. After heating the reaction at reflux for 4 h, the solvent was evaporated. The residue was suspended in CH2Cl2 (100 mL) at 0° C. and triethylamine (25 mL) was added, followed by the dropwise addition of methanesulfonyl chloride (7.75 mL, 100 mmol). The reaction was stirred at rt for 1 h, poured into ice H2O, extracted with CH2Cl2, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel eluting with 1% MeOH/CHCl3. The title compound was isolated as a white solid (11.8 g, 74%): 1H NMR (CDCl3): d 8.03 (d, 2H); 7.42 (d, 2H); 4.9 (br t, 1H); 4.38 (d, 2H); 3.92 (s, 3H); 2.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[NH:8][C:7](=O)[C:6]=2[CH:13]=1.O.[NH2:16][NH2:17]>C(O)COCCO>[Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]=[C:7]([NH:16][NH2:17])[C:6]=2[CH:13]=1
Reactant: NN
Reactant: O=C1NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Solvent: OCCOCCO
Solvent: O
Product: NNC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Yield: 59.6 %

Procedure:
50.2 g (0.2 mol) of 5,6-dichloro-3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide in 200 ml of diethylene glycol are stirred with 35 g of hydrazine hydrate for 30 hours at 160° C. to 165° C. Working up analogously to Example 1 gives 31.7 g (63% of theory) of 5,6-dichloro-3-hydrazino-1,2-benzisothiazole 1,1-dioxide which decomposes at 276° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[C:11]([C:10]1[C:3]2[C:2]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)#[N:12]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(N3CCC(NC(=O)c4ccccc4)CC3)ncnc21
Reaction time: 0.75 h

Procedure:
4-chloro-7-({[2-(trimethylsilyl)ethyl]oxy}methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile D43 (100 mg) and N-4-piperidinylbenzamide (86 mg, 0.42 mmol, commercially available from e.g. Fluorochem, Alfa Aesar and Apollo) were dissolved in NMP and then N,N-diisopropylethylamine was added dropwise. The reaction mixture was carried out in the microwave at 120° C. for 45 minutes. The reaction mixture was poured onto water extracted with EtOAc (2×60 ml). Organic layers were washed water (3×20 ml), brine (30 ml), dried (MgSO4), filtered and solvent removed. Crude product obtained was purified by flash chromatography on silica gel eluting with Pet Eth/EtOAc 3/1-2/1 to give the desired product D44 in 69 mg. LCMS [MH+] 477.2@1.80 min (5 min run)
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH:12]([CH3:24])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C.O>C(#N)C>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH:12]([CH3:24])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(Br)CCC(=O)N1CCC(C)CC1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)CCC(C)Sc2nc3ccccc3[nH]2)CC1
Yield: 21.3 %

Procedure:
0.15 g of 2-mercaptobenzimidazole and 0.26 g of 1-(4-bromovaleroyl)-4-methylpiperidin were suspended in acetonitrile, and the suspension was added with 0.17 ml of triethylamine and refluxed for 7 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:methylene chloride=1:10) to obtain 0.07 g of the title compound as oil (yield: 21%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) and 3-fluorobenzyl bromide according to General Procedure B. Yield 428 mg (56%), MP 137° C.; 1H-NMR (DMSO-d6): δ 3.73 (m, 4H), 3.93 (m, 4H), 5.52 (s, 2H), 7.06-7.10 (m, 3H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.33 (m, 1H), 7.50 (d, J=3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.17 (dd, J=2.8, 9.2 Hz, 1H), 8.77 (d, J=2.8 Hz, 1H); EIMS: 492 (M+1). Anal (C25H19F2N5O2S) C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)O[CH:10]=1.O.[NH4+:21]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[NH:21][CH:10]=1
Reactant: O=c1cc(COC2CCCCO2)occ1CCCO
Reactant: [NH4+]
Solvent: CCO
Solvent: O
Product: O=c1cc(COC2CCCCO2)[nH]cc1CCCO
Reaction time: 0.5 h

Procedure:
To a solution of 1.2 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 5 mL of ethanol, 16 mL of 25% ammonium water was added, and the mixture was heated under reflux while stirring for 9 hours 30 minutes. The solvent was distilled off under reduced pressure, and the resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=95:5 to 90:10 to obtain 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-one as a brown oily substance.