Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:17]=[C:18]2[C:35](=[CH:36][CH:37]=1)[O:34][C:21]1([CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]1)[CH2:20][C:19]2=[O:38]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:17]=[C:18]2[C:35](=[CH:36][CH:37]=1)[O:34][C:21]1([CH2:26][CH2:25][N:24]([CH2:27][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:23][CH2:22]1)[CH2:20][C:19]2=[O:38]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrCCCc1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and (3-bromopropyl)benzene (0.134 ml, 0.88 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (3 ml), and the mixture was stirred at RT for 24 h and then under reflux for 18 h. The solvent was removed and the crude mixture was purified by column chromatography (eluent:DCM/MeOH 97:3) to give (E)-3-{1′-(3-phenyl-propyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (173 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[OH-].[K+].[CH3:16]I>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: COCCCNC(=O)OC(C)(C)C
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: COCCCN(C)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
A suspension of carbamate 270 (5.0 g, 26.4 mmol), crushed KOH (3.8 g, 67.7 mmol) in MeI (15 mL) was stirred at 20° C. for 72 h under N2. The solution was filtered through Celite, washed with DCM (2×50 mL) and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (30-50%) of EtOAc/pet. ether, to give carbamate 271 (2.0 g, 37%) as a colourless oil: 1H NMR δ 3.38 (t, J=6.3 Hz, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.28 (t, J=7.0 Hz, 2H, CH2O), 2.85 (s, 3H, NCH3), 1.78 (tt, J=7.0, 6.3 Hz, 2H, CH2), 1.46 [s, 9H, C(CH3)3]; MS (APCI) m/z 104 (MH+-tBuCO2, 100%); HRMS (FAB+) calcd for C10H22NO3 (MH+) m/z 204.1600, found 204.1605.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=O.O1CCCC1.[OH-].[Al+3].[Li+].[OH-].[OH-].[OH-]>O>[Cl:32][C:7]1[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=[C:5]([CH2:3][OH:2])[CH:6]=1
Reactant: COC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Agent: [Al+3]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
0.49 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid(71) (1.12 mmol) prepared in Example 58 was added to 5 mL of tetrahydrofuran, and cooled to −80° C. 0.09 g of lithium aluminum hydroxide (2.24 mmol) was slowly added thereto. After stirring for 2 hours, the temperature of the reactant was slowly raised to room temperature, and further reacted 2 hours. A small amount of water was added thereto terminate the reaction, and concentrated under reduced pressure. Then, the resultant was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.44 g of yellow crystal, [3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-yl]-methanol compound (yield 93%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:26][N:25]([CH3:27])[CH2:24][CH2:23][C:9]=3[N:10]([CH2:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)(O)[CH3:15])[C:11]=2[CH:12]=1)([CH3:3])[CH3:2]>O=S(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:26][N:25]([CH3:27])[CH2:24][CH2:23][C:9]=3[N:10](/[CH:13]=[C:14](/[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)\[CH3:15])[C:11]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c3c(n(CC(C)(O)c4ccncc4)c2c1)CCN(C)C3
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3ccc(C(C)C)cc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(7-Isopropyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol (100 mg, 0.2 mmol) was dissolved in SOCl2 (1.0 mL) and the reaction was stirred at RT for 2 h. After completion of reaction (as monitored by TLC) reaction mixture was concentrated under vacuum and saturated bicarbonate solution was added. The desired compound was extracted with EtOAc, organic layer washed with water, dried over sodium sulfate and concentrated under vacuum. The crude compound was purified by reverse phase chromatography. Yield: 68 mg. 1H NMR (DMSO, oxalate salt) δ (ppm): 8.62 (d, 2H), 7.70 (d, 2H), 7.48 (s, 1H), 7.42 (d, 1H), 7.05 (m, 2H), 4.40 (m, 2H), 3.58 (m, 2H), 3.05 (m, 3H), 2.95 (s, 3H), 1.95 (s, 3H), 1.25 (d, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([O:13][PH:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[PH](O)CCCCc1ccccc1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=[PH](CCCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110 %

Procedure:
To a solution of the compound of example 80 (1.75 g, 8.83 mmol) in dry CH2Cl2 (40 mL) was added benzyl alcohol (1.83 mL, 17.7 mmol), DMAP (108 mg, 0.88 mmol) and EDC (1.91 g, 10.0 mmol). The mixture was then stirred at room temperature for 18 h. The mixture was concentrated in vacuum, taken-up in ethyl acetate and washed with NaHCO3 (5%) and H2O. Drying (Na2SO4) and concentration gave 2.8 g of a pale yellow oil which was purified by flash chromatography (SiO2, ethyl acetate:hexane (1:1)) to give 1.92 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])C)[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2]>CO.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([NH:11][CH:13]([CH3:15])[CH3:14])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:17]1=[O:32]
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 14 h

Procedure:
Example 6, Alternative Preparation, Step 1: To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (0.090 g, 0.209 mmol; see Example 1, Step 8) in MeOH (10 mL) was added ˜100 mg of 10% Pd/C (50%, wet). The mixture was stirred under H2 (50 psi) for 14 h. The catalyst was filtered off and the solvent was evaporated to give N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropylamino)cyclohexyl)acetamide as a foamy solid residue (50 mg, 0.169 mmol). This material was dissolved in i-PrOH (2 mL), and the resultant solution was charged with 4-phenoxy-6-(trifluoromethyl)quinazoline 1-oxide (103 mg, 0.169 mmol; see Example 5, Alternative Preparation, Step 2) and N,N-diisopropylethylamine (0.059 ml, 0.337 mmol). The vessel was sealed under argon atmosphere and heated in a microwave for 1 hr at 120° C. The reaction was evaporated to give an oily residue, which was purified by automated flash chromatography to give a yellow solid. This was re-crystallized from CH2Cl2-hexane to afford the desired 4-((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylamino)-6-(trifluoromethyl)quinazoline 1-oxide (1st crop, 43.5 mg and 2nd crop, 3.1 mg). LC/MS found: (M+H)+=509.32. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.99 (s, 1H), 8.81 (s, 1H), 8.62 (d, J=9.0 Hz, 1H), 8.33 (dd, J=9.0, 1.6 Hz, 1H), 5.28 (t, J=8.3 Hz, 1H), 4.56 (brs, 1H), 4.02 (brd, 1H), 3.63 (m, 2H), 3.18 (brs, 1H), 2.55 (m, 1H), 2.27 (m, 1H), 2.03 (s, 3H), 1.97-1.67 (m, 7H), 1.16 (d, J=5.5 Hz, 3H), 1.15 (d, J=5.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:25])([C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:25])([C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:18])[F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[NH:28][N:27]=[N:26][N:14]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: N#CCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cc2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 135 °C
Yield: 44.9 %

Procedure:
A mixture of 2,2,3,3,4,4,5,5,5-nonafluoro-N-[4-(cyanomethyl)phenyl]pentanamide (6.8 g), sodium azide (5.56 g), ammonium chloride (4.53 g) and dimethylformamide (100 mL) were heated in a 135° C. oil bath under a nitrogen atmosphere overnight. Enough water was added to the hot reaction mixture to dissolve all suspended salts, the mixture was cooled to room temperature and more water was added until a precipitate formed. The solid was collected, washed with water and air dried. Recrystallization from ethylacetate/diethyl ether mixture yielded 3.4 g of the title compound as white flakes, m.p. 173°-174° C. The filtrate produced a second crop of 1.1 g of the title compound.
Reaction SMILES: [C:1]1([CH:7]([CH:9]([C:11]([OH:13])=[O:12])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(=O)(O)[O-].[Na+]>[C:14]([NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]([C:11]([OH:13])=[O:12])[OH:10])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(c1ccccc1)C(O)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NC(c1ccccc1)C(O)C(=O)O)c1ccccc1

Procedure:
reacting said 3-phenyl-isoserine with said benzoyl chloride in sodium bicarbonate to form N-benzoyl-3-phenyl-isoserine;
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([CH:11]1[CH2:16][S:15][CH2:14][CH2:13][N:12]1[C:17]([O-:19])=O)=[O:10])C(OC)=O.C(O)(C(F)(F)F)=O>ClCCl>[OH:1][CH2:2][CH:3]1[C:17](=[O:19])[N:12]2[CH:11]([CH2:16][S:15][CH2:14][CH2:13]2)[C:9](=[O:10])[NH:8]1
Reactant: COC(=O)[C@@H](CO)NC(=O)C1CSCCN1C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(CO)C(=O)N2CCSCC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a solution of the crude 1,1-dimethylethyl (3R or S)-({[(1R)-1-(hydroxymethyl)-2-(methyloxy)-2-oxoethyl]amino}carbonyl)-4-thiomorpholinecarboxylate (D26) in 20 mL of dichloromethane were added 10 mL of TFA. The reaction mixture was stirred at room temperature for 4 hrs. The solvent was removed under reduced pressure and the residue was taken up in MeOH and loaded on a SCX cartridge. The fractions eluted with methanolic ammonia were collected, the volume was reduced and the solution was stirred at 50° C. for 45 min. Then it was irradiated three times by microwave [set parameters: T=80° C., t=10 min (1×); T=120° C., t=5 min (2×)]. The solvent was removed and after 2 days the crude revealed the formation of a white solid. So it was precipitated with DME and it was collected by filtration, washing with Et2O, to give the 1st batch of the title compound (120 mg, y=28% over 2 steps). The filtered solution was evaporated to dryness and the resulting crude, dissolved in DME, was irradiated two times by microwave (set parameters: T=130° C., t=30 min). After filtration, the 2nd batch of the title compound was isolated as a brownish solid (94 mg, y=22% over 2 steps). The filtered solution was treated in the same way as before and after four microwave irradiation [set parameters: T=130° C., t=30 min (3×) and t=90 min (1×)] the 3rd batch of the title compound was isolated as a brownish solid (50 mg, y=12% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[C:34](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:34])[C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a mixture of 0.93 g of methyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, 0.31 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was added 0.58 g of methyl iodide, and the mixture was stirred at room temperature for 2 hours. Then 50 ml of diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.82 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][OH:14].[CH3:15]O>>[F:1][C:2]1[C:3]2[N:11]([CH2:12][CH2:13][OH:14])[CH:15]=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1NCCO
Reactant: CO
Product: OCCn1cnc2cccc(F)c21

Procedure:
To a solution of 2-[(2-fluoro-6-nitrophenyl)amino]ethanol (0.78 g ) in methanol (15 mL) 10% palladium on carbon (200 mg) was added. The mixture was hydrogentated at hydrogen pressure 1 bar until the consumption of hydrogen gas ceased (60 min). The reaction mixture was filtered through a pad of Celite, which was further washed with methanol and acetonitrile. The filtrate was concentrated to dryness and the residue was dissolved in formic acid (4 mL). The solution was transferred into a microwave vial, which was sealed and irradiated for 15 min at 135° C. The solvent was removed in vacuum, the residue was dissolved in methanol (4 mL) and a 7 M solution of ammonia in methanol (4 mL) was added. After 10 min the mixture was concentrated to dryness and the residue was purified on a short silica column. Yield 0.65 g (93%). MS (ESI) m/z 181.1 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm: 3.60 (t, J=5.3 Hz, 2H), 4.21 (t, J=5.3 Hz, 2H), 6.92 (dd, J=12.1, 8.1 Hz, 1H), 7.02 (m, 1H), 7.34 (d, J=8.1 Hz, 1H), 8.03 (s, 1H), 8.26 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][O:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.O>[CH2:12]([O:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][OH:15])[CH3:13]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-O-ethylserinate (2.7 g, 10.9 mmol) in THF (40 mL) was added lithium aluminum hydride (0.84 g, 22 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was diluted with water, filtered, and concentrated under reduced pressure to give tert-butyl (1-ethoxy-3-hydroxypropan-2-yl)carbamate which was used without further purification. MS ESI calc'd. for C10H22NO4 [M+H]+ 220. found 220. 1H NMR (400 MHz, CDCl3) δ 5.21 (s, 1H), 3.78-3.59 (m, 3H), 3.58-3.56 (m, 2H), 3.52-3.45 (m, 2H), 1.44 (s, 9H), 1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:8][C:9]([O:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23]Br)=[N:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C(O)C>[C:4]([O:8][C:9]([O:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23][C:1]#[N:2])=[N:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: COc1ccc2c(CBr)nn(OC(=O)OC(C)(C)C)c2c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(CC#N)nn(OC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
KCN (5.73 g, 88 mmol) in 23 ml of H2O was added dropwise at 0° C. to 1-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-bromomethyl-1H-indazole (10.5 g, 30.08 mmol) in 80 ml of ethanol and stirred at room temperature for 1 h 30. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4. Concentration and precipitation in diisopropyl ether gave the expected product (4.42 g, 50% as solid).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(C(F)(F)F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][NH:6]C.[C-]#N.[K+].[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CO>[CH3:1][N:2]([CH3:3])[C:18]1([C:5]#[N:6])[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CNC
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reaction time: 65 h

Procedure:
200 ml of methanol, 1680 ml of aqueous dimethylamine solution (40 percent by weight), 303 g of dimethylamine hydrochloride and 200 g of potassium cyanide were added to 200 g of 1,4-dioxa-spiro[4.5]decan-8-one, and stirring was carried out for about 65 hours. The resulting white suspension was extracted four times using 800 ml of ether each time, the combined extracts were concentrated, the residue was taken up in about 500 ml of dichloromethane and the phases were separated. The dichloromethane phase was dried over sodium sulfate, filtered and concentrated. 265 g of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile were obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH3:26])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH3:26])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(N)cc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 71.8 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (347 mg, 1.12 mmol) was reacted with tert-butyl 2-(4-aminophenyl)propan-2-ylcarbamate (420 mg, 1.68 mmol) to afford the desired product (422 mg, 63%) as a yellow solid: ESI MS m/z 524 [C27H30BrN3O3+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[NH:21][C:22](=[O:24])[CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[N:21]([CH2:26][CH2:27][O:28][CH3:29])[C:22](=[O:24])[CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(C(C)=O)c1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.5 mmol) in N,N-dimethylformamide (100 mL) was added dropwise a solution of N-[2-(benzyloxy)-4-bromo-6-nitrophenyl]acetamide (13.5 g, 37.1 mmol, Step 1) in N,N-dimethylformamide at 0° C. over 10 minutes. After stirring at 0° C. for 20 minutes, 1-bromo-2-methoxyethane (7.21 g, 51.9 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the mixture was poured onto water, and the aqueous layer was extracted with ethyl acetate/toluene (3:1). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:1) to afford the title compound as a gray solid (12.1 g, 77%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=O.N1CCCCC1>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:23][C:15]1[NH:14][C:22]2[C:17]([CH:16]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:3])[CH3:2]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of 5-acetyl-2-oxindole (88 mg), indole-2-carbaldehyde (87 mg) and piperidine (4 mg) in ethanol (2 mL) was held in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid which formed was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 133 mg (88% yield) of 5-acetyl-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as an orange solid.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C(N(CC)CC)C>[Br:18][CH:19]([CH3:23])[C:20]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:21]
Reactant: CC(Br)C(=O)Br
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Br)C(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Into 50 ml of tetrahydrofuran, were added 3.5 g of 2-amino-4-phenylthiazole and 2.0 g of triethylamine. The mixture was cooled to 0°--5° C. Then, 4.3 g of α-bromopropionylbromide was dropped to the solution mixture. After the completion of the dropwise addition, the solution mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The residue was taken up in chloroform and washed with water. Upon removal of chloroform, a crude reaction product was obtained. It was thereafter subjected to silica gel chromatography and then eluted with a chloroform/methyl alcohol (40:1) mixed solvent. It was then recrystallized from an ether/cyclohexane mixed solvent, thereby obtaining 4.2 g of 2-(α-bromopropionylamino)-4-phenylthiazole.