Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][NH:23][C@@H:22]([CH:25]([CH3:27])[CH3:26])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[F:28][C:29]([F:39])([F:38])[C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][N:23]([CH2:36][C@H:33]4[CH2:32][CH2:31][C@H:30]([C:29]([F:28])([F:38])[F:39])[CH2:35][CH2:34]4)[C@@H:22]([CH:25]([CH3:26])[CH3:27])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C[C@H]2CC[C@H](C(F)(F)F)CC2)[C@H]3C(C)C)nc1
Temperature: 70 °C

Procedure:
To a solution of (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (3.6 g, 9.25 mmol), trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (3.3 g, 18.5 mmol) in anhydrous MeOH (100 mL) was added acetic acid dropwise until the pH was between 6 and 7. Sodium cyanoborohydride (1.7 g, 27.75 mmol) was added portionwise at rt. The mixture was heated to 70° C. for 1 h. Upon completion, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), then the organic phase was washed with water (3×100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%), then further purified by a chiral column using the following conditions: instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; column: AD 300 mm×50 mm, 10 μm; mobile phase: A: supercritical CO2, B: iPrOH (0.05% diethylamine), A:B=60:40 at 200 mL/min; column temp: 38° C.; nozzle pressure: 100 bar; nozzle temp: 60° C.; evaporator temp: 20° C.; trimmer temp: 25° C.; wavelength: 220 nm. Isomer SFC tR=2.28 min in 12 min chromatography was isolated as the major isomer, which was then further purified by reverse-phase HPLC to give (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (2, HCl salt) as a light yellow solid. LC-MS tR=0.69 min in 1 min chromatography, MS (ESI) m/z 553.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.12 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.36-8.32 (m, 2H), 7.75 (d, J=8.0 Hz, 1H), 5.16 (d, J=15.6 Hz, 1H), 4.89-4.87 (m, 2H), 4.73 (d, J=15.2 Hz, 1H), 3.42-3.34 (m, 3H), 3.31-3.28 (m, 2H), 2.58-2.51 (m, 1H), 2.20-1.90 (m, 6H), 1.50-1.39 (m, 2H), 1.33 (d, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 1.24-1.20 (m, 2H), 1.10 (d, J=6.8 Hz, 3H). HCl preparative HPLC method mobile phase A: water with 0.05% HCl; mobile phase B: CH3CN; flow rate: 80 mL/min; detection: UV 220 nm/254 nm; column: Phenomenex Gemini C18 (250 mm×50 mm×5 μm); column temperature: 30° C.
Reaction SMILES: [N:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:15]OC(OC)N(C)C.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1>C(O)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:15]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:33]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)CC(=O)CN1CCOCC1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cn(-c2ccc(OC)cc2)nc1CN1CCOCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To methyl 4-(morpholin-4-yl)-3-oxobutanoate (7.0 g) synthesized in the above-mentioned (1) was added dimethylformamide-dimethylacetal (4.9 mL), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, ethanol (200 mL) and 4-methoxyphenylhydrazine hydrochloride (6.3 g) were added, and the mixture was stirred at 100° C. for 3 hr. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (10.6 g, 93%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28](O)=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:56][CH2:57][CH2:58][NH2:59].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:56][CH2:57][CH2:58][NH:59][C:28]([C:14]1[N:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=2)[CH:16]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:31])=[O:10])[N:13]=1)=[O:29]
Reactant: NCCCl
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCCl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
90.6 mg (0.2 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 500 μl of DMF, and 36.65 mg (0.3 mmol) of DMAP and 114 mg (0.3 mmol) of HATU are added. After stirring at RT for 5 minutes, a solution of 46.4 mg (0.4 mmol) of 1-chloro-2-aminoethane and 25.8 mg (0.2 mmol) of N,N-diisopropylethylamine in 500 μl of DMF is added dropwise. The reaction mixture is stirred at RT for 6 h, then filtered and purified by preparative HPLC (method 9). The product-containing fractions are evaporated in vacuo.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:9]=[C:10](/[CH:15]=C/C(O)=O)[CH:11]=[CH:12][C:13]=1[F:14].CN(C)C=O>ClCCl>[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:1][C:2]([Cl:4])=[O:3])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0-5° C., oxalyl dichloride (25.7 g, 202.36 mmol, 3.00 equiv.) was added to a mixture of (E)-3-(3,4-difluorophenyl)acrylic acid (12.4 g, 67.38 mmol, 1.00 equiv.), N,N-dimethylformamide (1 mL), and dichloromethane (150 mL). The solution was stirred at ambient temperature for about 2 hours, and then concentrated in vacuo to give the title product, which was used in the next step without any further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1.[CH3:18][O:19][C:20](=[O:32])[C@H:21]([N:29]=[C:30]=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1>[CH3:18][O:19][C:20](=[O:32])[C@H:21]([NH:29][C:30]([O:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][C:6]=2[CH:7]=1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 50 °C
Yield: 63.7 %

Procedure:
A mixture of 2-hydroxmethyl-5-phenyl-benzofuran 17 (1.20 g, 5.85 mmole), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (1.2 g, 5.9 mmole), triethylamine (1.7 ml), and THF (30 ml) was heated to 50° C. under a nitrogen atmosphere for 6 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography giving about 1.6 g of (R)-2-(phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 18, mp. 85-86° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[NH:15]2)=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(=[O:35])[NH:33][C:32](=[O:34])[CH:31]=[CH:30]1>>[CH2:1]([O:8][C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:12]2[C:13]3[CH:30]4[C:29](=[O:35])[NH:33][C:32](=[O:34])[CH:31]4[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH2:18][C:14]=3[NH:15][C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1cc2cc(C=Cc3ccccc3Cl)[nH]c2cc1OCc1ccccc1
Product: COc1cc2c3c([nH]c2cc1OCc1ccccc1)CC(c1ccccc1Cl)C1C(=O)NC(=O)C31
Yield: 87 %

Procedure:
Reaction of the diene (155) prepared as described in example 255 with maleimide using the procedure described in example 69 gave the adduct (161) as a tan powder (87%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([I:16])[CH:3]=1.[H-].[Na+].[CH3:19]I.O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[C:4]([I:16])[CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To the solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)carbamate (61 g, 0.172 mol) in 300 mL of anhydrous THF was added 60% NaH (7.6 g, 0.189 mol) at 0° C. under N2 atmosphere. After the addition was finished, the solution was stirred for 30 min, and then the solution of MeI (26.92 g, 0.189 mol) in 100 mL of dry THF was added. Then the solution was stirred at 0° C. for 3 hrs. TLC indicated the reaction was over. Water was added for quench, and EtOAc was added to extract twice. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to afford 63 g of crude tert-butyl (6-chloro-4-iodopyridin-3-yl)(methyl)carbamate used into the following de-protection without the further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCCl>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:18]2[CH2:19][CH2:20][C:14]3[NH:13][C:12]4[N:11]=[CH:10][CH:9]=[C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:16]=4[C:15]=3[CH2:17]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (25 mg, 0.09 mmol), 4-fluorobenzoyl chloride (18 mg, 0.11 mmol), and triethylamine (0.04 mL, 0.28 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 7 (33 mg, 90% yield) as a tan solid. LC-MS (M+H=388, obsd.=388).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: C=CC(=O)O
Reactant: Fc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Yield: 57.4 %

Procedure:
Thus, a solution of 5-fluoroindole (1.35 g, 0.010 mole) in 10 mL of acetic acid containing acrylic acid (1.5 mL, 0.022 mole) and acetic anhydride (1.9 mL, 0.02 mole) was heated (oil bath) at 90° C. under Ar for 5 days. The volatiles were then removed in vacuo and the residue was taken up in 3 N NaOH. Insoluble material was removed by filtration and the filtrate was acidified with conc. HCl and then extracted with CH2Cl2. The organic extract was dried (Na2SO4) and evaporated to give the product (1.19 g, 57%) as a solid which was used without further purification: IR (neat) 3420, 1710 cm-1 ; 1Hnmr (200 MHz, CDCl3) δ 7.94 (br s, 1H), 7.28-7.18 (m, 3H), 7.05 (d, J=2.5 Hz, 1H), 6.93 (dt, J=9.0, 2.6 Hz, 1H), 3.05 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Cl:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Temperature: 62 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (560 mg, 2.89 mmol), 1-Bromo-2-chloro-ethane (0.36 mL, 4.39 mmol), and cesium carbonate (2.81 g, 8.67 mmol) in acetonitrile (20 mL) stirred at 62° C. for 4 hrs. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (664 mg, 90%). 1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1H), 7.79 (s, 1H), 4.45 (t, 2H), 3.90 (t, 2H), 1.34 (s, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[F:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:15][CH:14]=[CH:19]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Product: Fc1cc(Br)c2ncccc2c1
Temperature: 150 °C

Procedure:
To a mixture of 2-bromo-4-fluoroaniline (commercially available, 7.0 g), glycerol (7.0 g) and m-nitrobenzene sulfonic acid sodium salt (13.0 g) was added 20 ml of 70% sulfuric acid dropwise. The reaction temperature was raised to 150° C. for 4 hr. The mixture then was cooled to room temperature, poured on ice water and filtered through celite. The filtrate was neutralized with NaOH and the resulting precipitate was collected by vacuum filtration to yield 3.47 g of the title compound as a light yellow solid; MP=75-78° C.; MS (ES) m/z (relative intensity): 227 (M+H)+ (100).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.O>O1CCCC1>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: C=C[Mg]Cl
Reactant: O=Cc1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)cc1
Yield: 99 %

Procedure:
1,550 ml (2.0 mol) of a 1.29 M solution of vinylmagnesium chloride in tetrahydrofuran were introduced into a 4 l stirred flask under nitrogen. Subsequently, while stirring under nitrogen at 30°-35° C., a solution of 222.0 g (1,764 mol) of 4-fluorobenzaldehyde in 2,000 ml of tetrahydrofuran was added over the course of 30 min, cooling the reaction mixture with ice. The mixture was then stirred at room temperature under nitrogen for 2.5 h. Subsequently, while stirring and cooling with ice, 180 ml of water were added, the mixture was filtered with suction, and the residue from the filter was washed 3x with 150 ml of tetrahydrofuran. The filtrates were combined, dried with sodium sulfate and concentrated. 265.7 g (99%) of product were obtained in the form of a yellow-brown oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH3:29][C:30]([C:33]1[N:38]=[CH:37][C:36]([C:39](=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][N:34]=1)([CH3:32])[CH3:31].O>C(OCC)C.CCCCCC>[CH3:29][C:30]([C:33]1[N:38]=[CH:37][C:36]([C:39](=[C:2]([CH3:3])[CH3:1])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][N:34]=1)([CH3:32])[CH3:31]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C(=O)c1cnc(C(C)(C)C)nc1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(=C(C)C)c1cnc(C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.5 molar solution of n-butyl lithium in hexanes (5.5 cm3) was added in portions to a suspension of isopropyltriphenylphosphonium iodide (6 g) in dry diethyl ether, whilst the temperature was maintained between -10° and -20° C. After stirring for 1 hour at this temperature, a solution of ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-2-oxo-acetate (3 g) in dry diethyl ether (15 cm3) was added in portions. The stirred reaction mixture was allowed to warm to the ambient temperature, and allowed to stir for 16 hours. The reaction mixture was poured into water and extracted into ethyl acetate. The combined organic extracts were washed, dried over anhydrous magnesium sulphate, and concentrated by removal of the solvent under reduced pressure to give a dark brown oil, which was subjected to chromotography on silica gel, using hexane containing 10% ethyl acetate (by volume), as eluent to give ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.4 g) as a clear oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH:42]1(N)[CH2:46]C[CH2:44][CH2:43]1.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:37]1([CH2:36][NH:35][CH2:34][CH2:33][N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]3)[CH:29]=[N:30]2)[CH2:44][CH2:43][CH2:42][CH2:46]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCC5CCCC5)c4)cc23)CC1
Yield: 40 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclopentanamine (37 mg, 0.43 mmol) for the 2-aminoethanol to afford 11 mg of the title compound (40%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH:32]=O)=[CH:24]2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH:32]=[C:7]3[C:6]4[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=4[C:13]4[C:8]3=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:24]2)=[CH:34][CH:35]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(=Cc1cn(Cc3ccc(Cl)cc3)c3ccccc13)c1ccccc1-2
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a solution of 2-nitrofluorene (250 mg, 1.18 mmol) in 20 mL of methanol was added 1-(4-Chloro-benzyl)-1H-indole-3-carbaldehyde (382 mg, 1.42 mmol) and KF—Al2O3 (189 mg, 1.18 mmol). The resulting mixture was stirred at 85° C. for 18 hrs. After that, TLC showed that 2-nitrofluorene was gone, and many solids were suspended in MeOH. 260 mg of CYD-2-21 was obtained as a yellow solid after filtration and recrystallization from CH2Cl2. One isomer: 1H-NMR (600 MHz, d6-DMSO) δ 8.96 (s, 1H), 8.41 (s, 1H), 8.27 (m, 2H), 8.18 (m, 3H), 8.09 (d, 1H, J=7.2 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz), 7.47 (m, 5H), 7.28 (t, 1H, J=7.2 Hz), 7.20 (t, 1H, J=7.2 Hz), 5.57 (s, 2H). Another isomer: 1H-NMR (600 MHz, d6-DMSO) δ 9.01 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.19 (m, 4H), 7.86 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz), 7.47 (m, 5H), 7.28 (t, 1H, J=7.2 Hz), 7.20 (t, 1H, J=7.2 Hz), 5.59 (s, 2H). 13C-NMR (150 MHz, d6-DMSO) δ 147.1, 146.6, 145.6, 142.9, 141.9, 141.0, 138.2, 138.0, 137.0, 136.8, 136.7, 136.4 (2C), 135.6, 132.7, 132.2, 132.1, 130.2, 129.9, 129.8, 129.7, 129.2, 129.1, 129.0 (2C), 128.4, 128.1 (2C), 127.9, 124.5, 124.1, 123.8, 123.2 (2C), 123.1, 122.4, 122.0, 121.7, 121.2, 121.0 (2C), 120.8, 120.6 (2C), 120.2, 118.8, 118.7, 116.2 (2C), 111.5, 111.4, 111.3 (2C), 49.4, 49.2.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[NH:9][C:4]=2[CH:3]=1.Cl.[CH3:15][O:16][NH2:17].[OH-].[Na+]>CCOC(C)=O>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:17][O:16][CH3:15])=[O:11]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
NMR Spectrum: (DMSO-d6) 6.88 (dd, 1H), 7.21 (ddd, 1H), 8.00 (dd, 1H), 11.87 (s, 1H). 7-fluoro-1H-3,1-benzoxazine-2,4-dione (0.85 g, 4.69 mmol) was added to stirred solution of O-methylhydroxylamine hydrochloride (1.960 g, 23.47 mmol) in a 2N aqueous solution of sodium hydroxide (11.73 ml, 23.47 mmol) at 25° C. The resulting solution was stirred at room temperature for 2 hours. The solution was diluted with EtOAc, washed sequentially with water and brine. The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM to afford 2-amino-4-fluoro-N-methoxybenzamide (0.390 g, 45.1%) as a white crystalline solid. NMR Spectrum: (DMSOd6) 3.67 (s, 3H), 6.30 (dd, 1H), 6.47 (ddd, 1H), 6.62 (bs, 2H), 7.37 (dd, 1H), 11.40 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:5]([CH2:6][NH2:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]([CH2:6][N:7]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH2:10][CH3:11])[CH:9]=1
Reactant: CCc1cc(Br)cc(CC)c1CN
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1cc(Br)cc(CC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
4-Bromo-2,6-diethylbenzylamine (90 mg, 0.37 mmol), 1,5-dibromopentane (56 pt, 0.41 mmol) and potassium carbonate (206 mg, 1.5 mmol) were suspended in dioxane (5 mL) and heated at 100° C. overnight. The reaction mixture was then cooled to ambient temperature, the solid removed by filtration and the filtrate concentrated in vacuo to afford an orange oil. The resultant oil was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as yellow oil (66 mg, 58%). 1H NMR (CDCl3, 300 MHz): 7.16 (s, 2H), 3.38 (s, 2H), 2.80-2.62 (m, 4H), 2.35 (s, 4H), 1.54-1.34 (m, 6H), 1.27-1.13 (m, 6H).