Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[OH:8].CI.[C:33](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:27])[F:28])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:33]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
A mixture of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 1, 100 mg, 0.23 mmol), methyl iodide (0.14 mL, 0.23 mmol), and potassium carbonate (31 mg, 0.23 mmol) in acetone (4 mL) was stirred at room temperature for 4 h. Excess potassium carbonate was removed and the reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 30% EtOAc/hexanes to afford 74 mg of 5-(5-(3-fluoro-4-methoxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. LCMS [M+1]+ 451.4
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:29][C:30]1[N:34]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:33]=[CH:32][C:31]=1[CH2:39]Br>C1COCC1>[Br:29][C:30]1[N:34]([C:35]([CH3:37])([CH3:36])[CH3:38])[N:33]=[CH:32][C:31]=1[CH2:39][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)n1ncc(CBr)c1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cnn(C(C)(C)C)c2Br)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (0.37 mL, 1.47 mmol) in THF (15 mL) was cooled to −78° C. and then treated with lithium bis(trimethylsilyl) amide (1.48 mL, 1.48 mmol, 1 M toluene), dropwise. The reaction was stirred 15 minutes at −78° C., warmed to 0° C. for 30 minutes and then cooled back to −78° C. A solution of 5-bromo-4-(bromomethyl)-1-tert-butyl-1H-pyrazole (335 mg, 1.13 mmol) in THF (10 mL) was added, the mixture was stirred 1 hour at −78° C., and then allowed to stir 18 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (20 mL), stirred 30 minutes at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by flash chromatography (5-40% ethyl acetate/heptane, 25 g silica gel) to yield 256 mg of 1-tert-butyl 4-ethyl 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate as a clear oil. +ESI (M+H) 474.2, (M+2+H) 476.2; 1H NMR (400 MHz, CDCl3, δ): 7.20 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.93 (br. s., 2H), 2.84 (m, 2H), 2.66 (s, 2H), 2.10 (d, J=12.5 Hz, 2H), 1.72 (s, 9H), 1.45 (m, 11H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CN(C=O)C>O>[N:17]([CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[N+:18]=[N-:19]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Under nitrogen, a solution of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene (1.2 g, 0.0037 mol), NaN3 (0.6 g, 0.0092 mol) and DMF (25 ml) was heated at 100° C. After 18 hours, the solution was cooled, poured into H2O, and filtered to yield 0.8 g of product. The filtrate was extracted with ethyl acetate (2x). The organic layers were dried, filtered and concentrated to dryness to yield an additional 0.4 g of product (75%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:6][N:7]=1.[H][H]>C(Cl)Cl.CO.[Pd]>[NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CCC4(CC3)OCCO4)cnc2N)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC4(CC3)OCCO4)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
To a solution of tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate (11 g, 25.7 mmol) in DCM (100 mL) and MeOH (100 mL) at room temperature was added Pd/C (5 g, 25.7 mmol) (10% in carbon, wet). The resulting mixture was vacuumed, and then refilled with hydrogen. The process was repeated three times. Then the reaction was stirred at room temperature under H2 atmosphere for 6 h. Catalyst was filtered out through Celite®, and washed with DCM. The filtrate was concentrated, and the residue was dissolved in DCM (60 mL), filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc/heptane to provide tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-yl)-2-fluorobenzoate (8.18 g, 19.04 mmol, 74%) as a light yellow solid. LCMS (m/z): 430.2 (MH+), 0.99 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-7.82 (m, 2H), 7.71-7.49 (m, 2H), 6.13 (s, 2H), 3.85 (s, 4H), 3.30 (s, 1H), 2.77-2.55 (m, 1H), 2.48 (dt, J=3.62, 1.91 Hz, 2H), 1.88-1.65 (m, 6H), 1.63-1.46 (m, 10H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=O.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[O:23].[OH-].[Na+]>C1COCC1>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]1[C:3](=[O:5])[CH:2]2[CH2:6][CH2:7][CH2:8][CH2:9][N:1]2[C:22]1=[O:23]
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: O=C(O)C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1N1C(=O)C2CCCCN2C1=O
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A mixture of pipecolinic acid (500 mg; 3.87 mmol), 2-methoxy-4-nitrophenylisocyanate (902 mg; 4.65 mmol) and 9:1 THF:2 M NaOH were reacted in a microwave vessel at 160° C. for 10 min. The reaction mixture was then cooled to rt and purified by column chromatography (1:1, EtOAc:hexanes) to afford 736 mg of 2-(2-methoxy-4-nitrophenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione, 1.1.1, (62%).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([S:8]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH:11]1([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:17])=[O:3])(=[O:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a solution of 3.47 g (13.2 mmol) of 2-cyclohexanesulfonyl-2-methyl-propionic acid ethyl ester in THF/water (4/1, 50 mL) were added 1.11 g (26.4 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer was cooled in an ice bath and then acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with DCM (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 2.96 g of 2-cyclohexanesulfonyl-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:36])[NH:33][C:32]3=[O:37])=[CH:38][CH:39]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COc1ccc(OC)c(-c2ccc(C(C)=O)cc2)c1
Agent: Cl
Product: COc1ccc(OC)c(-c2ccc(C(C)=NOCCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Yield: 92.7 %

Procedure:
Following a procedure similar to that described in Example 40(f), 256 mg of 4'-(2,5-dimethoxyphenyl)acetophenone were reacted with 382 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 482 mg of the title compound as an amorphous solid, melting at 47°-52° C. (softening point).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([CH3:24])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:25]OS([O-])=O.[K+].O>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([CH3:24])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]([OH:25])=[O:5]
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C=O)c(F)c4)c3c2)o1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A suspension of 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzaldehyde (0.693 g, 2.15 mmol) and oxone (registered trade mark) (1.99 g, 3.23 mmol) in N,N-dimethylformamide (25 mL) was stirred overnight at room temperature. The reaction mixture was poured into water, and the precipitate was collected by filtration, dried and recrystallized from tetrahydrofuran to give the title compound (555 mg, yield 76%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][C:44](Cl)=[O:45]>>[CH2:34]([N:33]([CH2:36][CH3:37])[CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:39]5[S:38][CH:42]=[CH:41][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:35]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCN(CC)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Product: CCN(CC)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 49 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(diethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 49% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (t, J=7.2 Hz, 6H) 3.2 (s, 4H) 3.5 (s, 2H) 3.9 (s, 2H) 4.3 (s, 2H) 6.5 (d, J=5.3 Hz, 1H) 6.6 (s, 1H) 7.0 (m, 2H) 7.1 (d, J=1.5 Hz, 1H) 7.3 (d, J=5.1 Hz, 1H) 7.4 (m, 2H) 7.5 (m, 1H) 7.6 (s, 1H) 7.7 (s, 1H) 7.9 (s, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (s, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.6 (s, 2H) 10.4 (s, 1H). ES-LC/MS m/z 618 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2].N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)C>[C:1]([CH:3]([N:16]1[CH2:21][CH2:20][N:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2]
Reactant: COc1ccc(C(C#N)N2CCNCC2)c(OC)c1OC
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)N1CCN(C(C#N)c2ccc(OC)c(OC)c2OC)CC1
Temperature: 25 °C

Procedure:
14.5 g. of N-(α-cyano-2,3,4-trimethoxybenzyl)piperazine was dissolved in 50 ml. of anhydrous diethyl ether and to the resultant solution was added 4 g. of pyridine. To the mixture was added dropwise 6 g. of ethyl chloroformate dissolved in 10 ml. of anhydrous diethyl ether over a period of about 30 minutes with ice cooling while the internal temperature was kept at 10° - 15°C. The mixture was further stirred at room temperature and filtered off to separate an insoluble matter. The filtrate was evaporated to give crude N-(α-cyano-2,3,4-trimethoxybenzyl)-N'-ethoxycarbonylpiperazine as an oily substance. This product was dissolved in toluene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from tetrahydrofuran-methanol afforded 14 g. of crystal having a melting point of 137.5° - 139.0°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.CO>CN(C)C=O>[CH:25]1([CH2:24][N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:27][CH2:26]1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cn(CC2CC2)nc(-c2ccnn2-c2ccccc2)c1=O

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in dimethylformamide (40 mL) was added 60% sodium hydride (596 mg) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hr. Then, (bromomethyl)cyclopropane (1.085 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and crystallized from methanol/ethyl acetate to give the title compound (2.12 g) as white prisms.
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[N:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([CH:17]=[O:18])=[CH:7]1)=[O:5].C([O-])(=O)C.[K+]>CN(C=O)C.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>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]3[C:4](=[O:5])[C:3]4[C:19]([C:7]3=[C:8]([CH:17]=[O:18])[C:9]=2[N:10]=1)=[CH:20][CH:21]=[CH:22][CH:2]=4
Reactant: COc1ccc2c(n1)c(C=O)cn2C(=O)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)c(C=O)c1n2C(=O)c2ccccc2-1

Procedure:
Under an argon atmosphere, 0.49 mmol of the compound obtained in Step B, 0.2 mmol of tetrakis(triphenylphosphine)palladium(0) and 0.49 mmol of potassium acetate in 15 ml of DMF are heated at 140° C. for 3 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated, and the residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]
Reactant: Nc1cc(F)ccc1Cl
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cc(F)ccc1Cl)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 47.5 %

Procedure:
2-chloro-5-fluoroaniline (119 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(2-chloro-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45 mg, 47%) as a white solid. Mass Spectrum: M+H+ 474. NMR Spectrum (DMSOd6): 1.62 (d, 3H), 2.74 (bs, 3H), 2.94 (bs, 3H), 3.51-3.65 (m, 4H), 3.69-3.79 (m, 4H), 5.06-5.16 (m, 1H), 5.61 (s, 1H), 5.99 (d, 1H), 6.27 (dd, 1H), 6.40 (ddd, 1H), 7.30 (dd, 1H), 7.59 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1)([O-])=O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Yield: 109.4 %

Procedure:
Added 253 mg 10% palladium on carbon to a round bottom flask under N2 and covered catalyst with 140 ml ethanol. To this added 2.49 g (8.18 mmol) 6-nitro-4-[(3-methylphenyl)amino]-3-quinolinecarbonitrile and 640 μl (20.4 mmol) anhydrous hydrazine. The mixture was heated to reflux for 2 hours 15 minutes and filtered hot through celite. Stripped solvent and dried in vacuo, giving 2.455 g of yellow solid: mass spectrum (electrospray m/e): M+H=275.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:40][CH:37]4[CH2:39][CH2:38]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Reactant: O=CC1CC1
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv), and piperidine (78 mg). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was diluted with 10 mL of dichloromethane and the resulting mixture was washed with saturated aqueous ammonium chloride, water and brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (20/1) gave 28.5 mg (17%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+, H-NMR (300 MHz, CDCl3, ppm): δ 8.54 (s, 1H); δ7.68 (d, 2H); δ7.20 (d, 2H); δ7.16 (d, 2H); δ6.95 (m, 1H); δ6.55 (d, 1H); δ5.52 (s, 2H); δ6.98 (m, 1H); δ4.76 (m, 1H); δ4.34 (m, 1H); δ3.82 (m, 1H); δ3.23 (m, 1H); δ2.01˜δ2.42 (m, 4H); δ1.88 (m, 1H); δ0.85˜δ1.21 (m, 4H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C@H:41]([OH:43])[CH3:42]>>[OH:43][C@H:41]([CH3:42])[CH2:40][NH:39][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])=[O:28]
Reactant: C[C@@H](O)CN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: C[C@@H](O)CNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 54.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26]#[N:27])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]([Si](C)(C)C)=[N+:30]=[N-:31]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14]([CH2:24][CH2:25][C:26]3[NH:31][N:30]=[N:29][N:27]=3)=[CH:15][CH:16]=[C:17]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(CCC#N)ccc2-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCc3nnn[nH]3)ccc2-c2ccccc2)cc1
Temperature: 110 °C
Yield: 62 %

Procedure:
To a stirred solution of 4-[2-(2-cyano-ethyl)-5-phenyl-pyrrol-1yl]-benzoic acid tert-butyl ester (2.31 mmol, 1.0 eq.) in toluene (12 ml) were added Azidotrimethylsilane (TMSN3) (4.62 mmol, 2.0 eq.) and Sn(Bu)2O (dibutyltin(IV) oxide) (0.23 mmol, 0.1 eq.). The resulting mixture was heated to 110° C. overnight. The solvent was evaporated in vacuo and the residue loaded onto a 40 g RediSep silica-gel column for purification. Gradient elution with methanol/DCM (0% to 7% methanol in DCM over 25 minutes) gave the product 4-{2-phenyl-5-[2-(1H-tetrazol-5-yl)ethyl]-pyrrol-1-yl}-benzoic acid tert-butyl ester as a light yellow oil after combination of the appropriate fractions and evaporation of the solvent in vacuo, 62% yield.