Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:2].Cl.C(OCC)(=O)C>[Pd].C(O)C>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(n1CC#N)CCCC2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2c(n1CCN)CCCC2
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A 200-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 1.28 g dry weight), 104h (3.00 g, 12.9 mmol), 12% hydrochloric acid (6.5 mL, 25 mmol), ethyl acetate (60 mL) and ethanol (40 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (4.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×20 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (150 mL) and 10% aqueous potassium carbonate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethanol (5 mL) to afford a 71% yield (1.71 g) of 104i as a white solid: mp 102-104° C.; 1H NMR (500 MHz, DMSO-d6) δ 6.61 (s, 1H), 6.22 (br, 2H), 4.15 (m, 4H), 2.77 (m, 2H), 2.59 (t, 2H, J=6.5 Hz), 2.42 (t, 2H, J=6.5 Hz), 1.70 (m, 2H), 1.62 (m, 2H), 1.23 (t, 3H, J=7.0 Hz); MS (APCI+) m/z 237.2 (M+H)
Reaction SMILES: Cl.[CH3:2][C@@:3]1([OH:8])[CH2:7][O:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([N:5]4[CH2:4][C@:3]([CH3:2])([OH:8])[CH2:7][O:6]4)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C[C@]1(O)CNOC1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(C(=O)N3C[C@](C)(O)CO3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
Following the same procedure in Example 3, Step A, using (4S)-4-methylisoxazolidin-4-ol hydrochoride (36.8 mg, 0.264 mmol), diisopropylethylamine (144 μL, 106.6 mg, 0.83 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (83.2 mg, 0.253 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (114.0 mg, 0.30 mmol). The mixture was stirred for 4 h at room temperature,and quenched by adding H2O (5 mL). Upon evapoartion, the desired title compound was purified by reversed-phase HPLC (C-18 column) using 20-50% CH3CN/H2O to give 74.9mg (56%) of a white solid. [a]D: −14.1° (c 0.17,EtOH). 1H NMR (400 MHz, CD3OD): δ 0.85 (t, J=7.52 Hz, 3H), 1.27 (m, 5H), 1.50 (s, 3H), 1.66 (m, 3H), 1.69 (s, 6H), 1.79 (m, 2H), 2.04 (q, J=7.42 Hz, 2H), 2.13 (m, 1H), 3.82 (d, J=11.33 Hz, 1H), 3.89 (d, J=8.40 Hz, 1H), 3.97 (m, 2H), 4.50 (d, J=7.62 Hz, 2H), 7.99.(m, 2H), 8.18 (s, 1H). MS (ESI) (M+H)+=414.2. Anal. Calcd for C24H35N3O3+1.30 TFA+2.00 H2O (597.83): C, 53.44; H, 6.79; N, 7.03. Found: C, 53.39; H, 6.64; N, 7.22.
Reaction SMILES: C(OC([N:11]1[CH:20]([C:21](=[O:32])[NH:22][CH2:23][C:24](=O)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(OC(N1C(C(=O)NCC(=O)C2C=CC=CC=2)CC2C(=CC=CC=2)C1)=O)(C)(C)C.O=P(Cl)(Cl)Cl>>[C:25]1([C:24]2[O:32][C:21]([CH:20]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][NH:11]3)=[N:22][CH:23]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(CNC(=O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2cnc(C3Cc4ccccc4CN3)o2)cc1

Procedure:
Dehydration of 3-(2-oxo-2-phenyl-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (prepared in a similar manner as 3-(2-oxo-2-phenyl-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert butyl ester of Example 1) with POCl3 yields the following intermediate compound:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>C(OCC)C>[C:1]1([N:15]2[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCOCC
Product: C1=C(N2CCC3(CC2)OCCO3)CCCC1

Procedure:
54 ml (0.5 mole) of cyclohexanone together with 200 ml (1.5 mole) of 1,4-dioxa-8-aza-spiro[4.5]decane III were dissolved in 0.5 l of diethyl ether and stirred for half an hour to form the compound 8-cyclohex-1-enyl-1,4-dioxa-8-aza-spiro[4.5]decane IV. 31 ml of titanium tetrachloride in 0.5 l of n-hexane were then added dropwise at 0° C. within 60 minutes. After the addition the reaction mixture was heated slowly to 20° C. and stirred for a further 24 hours. The precipitate formed was filtered off under suction and discarded. The filtrate was concentrated by evaporation and directly reacted further. The yield was 83 g (0.37 mole, 71%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[Br:13][CH2:14][CH2:15]Br.O>CN(C=O)C>[Br:13][CH2:14][CH2:15][NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(NCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
To a suspension of 60% NaH (5.93 g, 247.08 mmol) in DMF (80 mL) taken in a one liter 2 neck round bottom flask fitted with a pressure equalizing addition funnel and a septum was added a solution of p-aminoacetophenone (20 g, 148.1 mmol) in DMF (60 mL) in drops through the pressure equalizing addition funnel under nitrogen atmosphere at 0° C. and the contents were stirred for 2 hours at 25° C. Then to the stirred solution was added 1,2-dibromoethane (97.48 g, 518.5 mmol) in drops and the contents were further stirred for another 18 hours at 90° C. The reaction mixture was cooled to 25-35° C. and was carefully added to cold water (650 mL) while stirring. The organics were extracted with ethylacetate (3×200 mL) and combined organics were washed with water (2×100 mL) followed by a brine wash. The separated organics were dried over Na2SO4 and concentrated under reduced pressure. The crude was chromatographed over silicagel by using 15-20% ethyl acetate/pet. ether (3 Lit), affording the title compound 5.1 g (14%) as a pale yellow solid. Mp: 92-94° C.
Reaction SMILES: Br[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]2[CH2:8][CH2:7][N:6]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:5](=[O:24])[C:4]=2[C:3]=1[CH3:25].[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]1[C:9]2[CH2:8][CH2:7][N:6]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:5](=[O:24])[C:4]=2[C:3]([CH3:25])=[C:2]1[C:30]1[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=1
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Temperature: 60 °C
Yield: 55.1 %

Procedure:
2-Bromo-1-(2-chlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (0.92 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.35 g, 2.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (350 mg) were dissolved in DME (46 ml) and 1 M Na2CO3 (12 ml)). The resulting solution was degassed and heated at 60° C. under nitrogen overnight. Water and EtOAc were added after cooling and the aqueous phase extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give a crude product that was purified by flash chromatography (heptane:EtOAc gradient) to afford 0.54 g (55%) of the product as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][O:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].ClS([N:27]=[C:28]=[O:29])(=O)=O.C(O)(=O)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:28]([N:11]1[C:10](=[O:14])[C:9](=[CH:8][C:7]2[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]([OH:18])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH2:13][O:12]1)(=[O:29])[NH2:27]
Reactant: CC(C)(C)c1cc(C=C2CONC2=O)cc(C(C)(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C=C2CON(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 100 °C
Yield: 52 %

Procedure:
To a solution of 212 mg (0.7 mmol) of the thus obtained 4-(3,5di-tert-butyl-4-hydroxybenzylidene)isoxazolidin-3-one in toluene (6 ml) was added 67 μl (0.77 mmol) of chlorosulfonyl isocyanate while being stirred with heating at 100° C. and allowed to react for 10 minutes. The reaction mixture was evaporated to give a residue, which was added with 4 ml of a acetic acid/water (2/1) mixture and stirred with heating at 100° C. for 10 minutes. The reaction mixture was evaporated to give a residue, which was dissolved in ethyl acetate. The reaction mixture was washed with water and saturated brine and evaporated under reduced pressure to give a residue, which was chromatographed on silica gel (n-hexane/ethyl acetate=2/1) to give 127 mg of the objective compound (Ie-1) in 52% yield. A part of product was recrystallized from a dichloromethane/n-hexane mixture.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[NH:8][C:9](=O)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:2]1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([NH:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[N:8]=1
Reactant: O=c1[nH]c(Nc2cc[nH]n2)cc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Temperature: 130 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
3-(1H-Pyrazol-3-ylamino)-2H-isoquinolin-1-one (7.4 g, 0.03 mol) and POCl3 (80 ml) were sealed in 4 different bottles (20 ml). The mixture was heated at 130° C. for 15 minutes under microwave irradiation. The mixture was concentrated, the residue was treated with 15 ml MeOH and stirred for 2 hours at room temperature. The solid was collected and dried to give product (4.7 g, 61% yield). LC-MS: 245(MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=C(NC(C2C(=O)N(C3C=CC(F)=CC=3)C=CC=2)=O)C=CC=1OC1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=CN=1.C(Cl)(=O)C([Cl:66])=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([Cl:66])=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c12
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid) (Compound J of Example 1) 475 mg, 2.04 mmol), was added oxalyl chloride (388 mg, 3 mmol), followed by one drop of DMF. The resulting mixture was stirred at rt for 1 h. The mixture was then concentrated in vacuo to afford the desired compound (500 mg, 100%) as a beige solid, which was used directly in the next step without further purification.
Reaction SMILES: O=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[CH2:8][CH2:7][C:6]3C=CC=C[C:5]=3[C:4]=2O1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[N:14]1([C:10]2[C:9]3[CH2:8][CH2:7][C:6]4[C:5](=[CH:27][CH:26]=[CH:25][CH:29]=4)[C:4]=3[C:29]3[C:25]4[C:9]([CH2:8][C:2]=3[C:11]=2[C:12]#[N:13])=[CH:4][CH:5]=[CH:27][CH:26]=4)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCC2)c2c(oc1=O)-c1ccccc1CC2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c2c(c3c(c1N1CCCC1)CCc1ccccc1-3)-c1ccccc1C2

Procedure:
A mixture of 2-oxo-4-(pyrrolidin-1-yl)-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile (292 mg), indanone-2 (132 mg) and NaH (28 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 220-222° C.; IR (KBr) 2204 cm−1 (CN); MS (ESI) 364 (M++2).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)[C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[C:17]([C:18]3[NH:22][N:21]=[CH:20][C:19]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40].O1CCOCC1>CO>[ClH:29].[ClH:40].[CH2:1]([N:8]([C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[C:17]([C:18]3[NH:22][N:21]=[CH:20][C:19]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:12]2=[CH:11][CH:10]=1)[CH2:30][CH2:31][OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)c1ccc2c(-c3[nH]ncc3-c3cccc(Cl)c3)c[nH]c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OCCN(Cc1ccccc1)c1ccc2c(-c3[nH]ncc3-c3cccc(Cl)c3)c[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of crude N-benzyl-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(4-(3-chlorophenyl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-6-amine (78 mg, 0.14 mmol) in methanol (5 mL) was added a 4M solution of hydrogen chloride in dioxane (5 mL, 20 mmol) and the solution stirred at room temperature for 2 hours. After this time the reaction was concentrated and the residue purified by preparative HPLC. Concentration of the product containing fractions afforded a solid that was re-dissolved in MeOH (5 mL) and treated with 2N HCl (2 mL). The solution was then re-concentrated, the residue co-evaporated with acetonitrile (5 mL) then dissolved in water (5 mL). Subsequent isolation by lyophilization afforded the title compound as a yellow solid in 25% yield over 2 steps.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]I.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[N:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:6][C:7]1[CH:8]=[C:9]2[CH:10]=[CH:11][N:12]([CH2:3][CH:2]([F:5])[F:1])[C:13]2=[N:14][CH:15]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)Cn1ccc2cc(Br)cnc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
1,1-Difluoro-2-iodoethane (2.19 g, 11.42 mmol) was added to a solution of 5-bromo,7-azaindole (1.5 g, 7.61 mmol) in DMF (30 mL) followed by cesium carbonate (4.96 g, 15.2 mmol), and the mixture was stirred at 70° C. for 1 h. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in reduced pressure and purified by flash chromatography using 5% ethyl acetate in hexane to afford title compound (1.3 g, 65%) as oil. 1H NMR (300 MHz, CDCl3): δ 8.33 (d, J=2.1 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 6.46 (d, J=3.6 Hz, 1H), 6.28-5.88 (tt, J1=3.9 Hz, J2=55.8 Hz, 1H), 4.60 (dt, J1=4.2 Hz, J2=14.1 Hz, 2H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CC[O:13][C:14]([C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O.O>C1(C)C=CC=CC=1.C(OCC)C>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[CH:14]=[O:13])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
At −78° C., a 1.2 M solution of diisobutylaluminum hydride (31.7 ml, 38 mmol) in toluene was added dropwise to a solution of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.02 g, 16.5 mmol) in diethyl ether (1.5 ml). The reaction mixture was stirred for 3 h at −78° C. Water (9.9 ml) was added dropwise. The reaction mixture was warmed to room temperature. The mixture was filtered through a plug of celite. The celite was washed with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo, to give 2.34 g of crude N-t-butyloxycarbonyl-(S)-prolinal, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3]1.[OH-].[K+].Br[CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CS(C)=O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:21][CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)=[CH:3]1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cn1cc(CN2CCNCC2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(CN2CCN(CCOc3ccc(C=O)cc3)CC2)c2ccccc21
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A suspension of 1-(1-methylindole-3-ylmethyl)piperazine (1.3 g) in dimethylsulfoxide (15 ml) and potassium hydroxide (0.63 g) was stirred for 30 min under nitrogen at 22° C. and then a solution of 4-[2-bromoethoxy]benzaldehyde (1.3 g) was added and stirring was continued for further 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with water, brine, dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed on silica gel using mixture of methanol: chloroform (1:9) as eluent to afford the pure product (0.76 g, 51%) as an oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(C)c2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(m-tolyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[CH:26]=[C:27]([C:30]#[N:31])[S:28][CH:29]=1>>[C:30]([C:27]1[S:28][CH:29]=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:26]=1)#[N:31]
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Product: CC1=CC(C)(C)Nc2ccc(-c3csc(C#N)c3)cc21
Yield: 90.6 %

Procedure:
This compound was prepared by General Method 2 from compound 9 (200 mg, 0.63 mmol) and 4-bromo-2-cyanothiophene (0.50 g, 2.65 mmol). The crude product was purified by prep. TLC (20×20 cm, 1000 μm, 25% ETOAc:Hexane) to afford 160 mg (91%) of Compound 452 as a yellow oil. Data for Compound 452: Rf 0.50 (silica gel, 25% EtOAc:hex); 1H NMR(400 MHz, CDCl3) 7.79 (s, 1H), 7.46 (s, 1H), 7.20 (s, 1H), 7.16 (d, J=8.3, 1H), 6.46 (d, J=8.3, 1H), 5.37 (s, 1H), 2.03 (s, 3H), 1.31 (s, 6H); IR (film, NaCl) 1159, 1381, 1402, 1449, 1476, 1499, 1609, 1653, 2216, 2915, 3294, 3584.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[C:8]([NH:12][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CC(C)(C)NCCCS(=O)(=O)O

Procedure:
To a solution of 1,3-propanesultone (20 g, 0.164 g) in toluene (100 mL) was added tert-butylamine (90 mL, 62.1 g, 0.85 mol). The mixture was stirred under gentle reflux for 1 hour. The precipitate was filtered, washed with diethyl ether and dried at 20-25° C. Yield 3-(tert-butylamino)propylsulfonic acid 32 g (approximately 100%), as white microcrystals, mp above 280° C., 1H NMR (D2O) δ 1.33 (s, 9H), 2.07 (p, J=7.6 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 3.15 (t, J=7.7 Hz, 2H); 13C NMR δ 21.3, 24.3, 39.4, 47.4, 56.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[H-].[Na+].C[Si](C)(C)CCO[CH2:30][Cl:31]>CN(C=O)C>[Cl:31][C:30]1[CH:11]=[C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=3)[CH2:6][CH:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:8]2)[CH:3]=[CH:4][CH:5]=1
Reactant: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 146.3 %

Procedure:
To a solution of 153A (627 mg, 2 mmol) in DMF (5 mL) at RT was added NaH (96 mg, 2.4 mmol) in portions. After addition, the reaction was stirred at RT for 30 min, and then 2-(trimethylsilyl)ethoxymethyl chloride (0.37 mL, 2.10 mmol) was added dropwise. After addition, the reaction was stirred at RT for 1 h, then quenched carefully with water. The mixture was extracted with EtOAc (3×30 mL), and the combined extracts washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (0-60%) in hexane to give the title compound as a white powder (620 mg, 70%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:31]3[CH2:32][CH2:33][N:28]([CH:26]=[O:27])[CH2:29][CH2:30]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(NCc3ccccc3)c2n1
Reactant: O=CN1CCNCC1
Product: O=CN1CCN(c2nc(N3CCSCC3)c3ncnc(NCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 181 from 8-benzylamino-2-chloro-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 94°-96° C. and N-formyl-piperazine.