Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26].C(=O)([O-])[O-].[Na+].[Na+].B(O)O>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C1COCC1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)c(F)c4)cc3CC[C@@H]12
Yield: 58.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,4-difluorophenylboronic acid (123 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. Additional palladium reagent and boronic acid was added, and the mixture was heated for an additional 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 130 mg (58%) of the title compound as a white solid. mp 143-148°. FDMS: m/e =341 α[D]589 =+65.12 (c=0.97, chloroform).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:11]([NH2:13])=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:13][CH2:11][CH:3]([NH2:2])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)C(N)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC(N)Cc1ccccc1
Yield: 92.5 %

Procedure:
To a stirred slurry of D,L-phenylalanine amide hydrochloride (50.0 g, 0.249 mole) in anhydrous THF (200 ml) at room temperature under a dry argon atmosphere was added a solution of lithium aluminum hydride (1000 ml-1.0M in THF, 1.00 mole) over a 30 minute period. The mixture was refluxed for 7.5 h and then quenched by the dropwise addition of H2O (200 ml) while cooling in an ice bath. The solid was filtered, washed with hot THF (2×500 ml) and then hot methanol (2×500 ml). The filtrate and washings were combined and the solvent was removed in vacuo. The resulting yellow oil was dissolved in CHCl3 and the solution was filtered and dried (MgSO4). The solvent was removed in vacuo to give 34.6 g (92% yield) of the crude product as a yellow oil which crystallized on standing: 1H NMR (CDCl3) δ 1.68 (br s, 4 H), 2.51 (m, 2 H), 2.79 (m, 2 H), 2.95 (m, 1 H), 7.24 (m, 5 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Product: COc1ccc(CCN2CCC(N3CCc4ccc(CNC(C)=O)cc43)CC2)cc1
Yield: 53.7 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 4-methoxyphenethyl bromide (240 mg) were treated as in Example 2 to give the title compound (200 mg) as a white powder (yield: 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(F)cc2)=NN1
Temperature: 80 °C
Yield: 86 %

Procedure:
In a round-bottomed flask, 4-(4-fluoro-phenyl)-4-oxo-butyric acid (4.90 g, 25.0 mmol) and hydrazine hydrate (1.70 ml, 35.0 mmol) were dissolved in ethanol (50 ml), and the reaction mixture was heated to about 80° C. for about ninety minutes. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The resulting solids were suspended and stirred in ethanol (10 ml) for ten minutes and the mixture was then filtered to give pure product (4.14 g, 21.5 mmol, 86% yield). LRMS ([M+H]+)=193.2; m.p. 191-193° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:33])([F:32])[F:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3C(F)(F)F)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-trifluoromethyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl.[C:18]1([O:24]C2C=CC=CC=2)C=C[CH:21]=[CH:20][CH:19]=1>>[CH2:13]([O:12][C:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]2[C:2](=[CH:16][CH:15]=1)[N:1]=[C:20]([CH3:21])[CH:19]=[C:18]2[OH:24])=[O:11])[CH3:14]
Reactant: CCOC(=O)CCCOc1ccc(N)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: CCOC(=O)CCCOc1ccc2nc(C)cc(O)c2c1
Yield: 42 %

Procedure:
To a stirring mixture of ethyl 4-(4-aminophenoxy)butanoate (3.12 g, 14 mmol) and acetoacetic ester (1.82 g, 14 mmol) was added a catalytic amount of hydrochloric acid and cyclized in refluxing diphenyl ether as described in Example 5a. The product was obtained as a light yellow solid (1.70 g, 42%). 1H NMR (400 MHz, DMSO-d6): 1.32 (3H, t, J=7.1 Hz), 2.15 (2H, m), 2.50 (3H, s), 2.62 (2H, t, J=7.3 Hz), 4.21 (4H, m), 6.09 (1H, s), 7.42 (1H, dd, J=9.0, 2.7 Hz), 7.58 (1H, d, J=2.7 Hz), 7.65 (1H, d, J=9.0 Hz), 11.8 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[O:2][CH3:1])#[N:12]
Reactant: COc1ccccc1N
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: COc1ccccc1NC(N)=NC#N

Procedure:
A solution of 2-methoxyaniline and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([OH:19])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21](O)[CH3:22]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([O:19][CH2:21][CH3:22])=[O:18])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
In ethanol (60 mL) was dissolved 3,5-di-t-butyl-4-hydroxyphenyl-acetic acid (8.0 g, 30.3 mmol). The solution was saturated with HCl gas and stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and then brine (100 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo to give 7.95 g (90%) of the product as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(N2CCN(CCCn3cnc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
1-(3-chloropropyl)-1H-benzimidazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, phenyl piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.1 g compound (I-7) with a yield of 63.2%. ESI-MS [M+H]+: m/z 321.2.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br.C(O)(=O)CC>O>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Cl)cc3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Solvent: O
Product: Clc1ccc2c(c1)CNC2
Yield: 51.3 %

Procedure:
1.0 g of 2-(p-toluenesulfonyl)-5-chloroisoindoline and 1.0 g of phenol were added to a mixture of 8 ml of 48% hydrobromic acid and 1.4 ml of propionic acid, and the mixture was refluxed for 6 hours. The resultant reaction mixture was diluted with 10 ml of water and extracted 2 times with 50 ml of ether. The water layer was basified with aqueous sodium hydroxide solution and extracted with 50 ml of ether 4 times. The extract was concentrated and the residue was purified by vacuum distillation (bath temperature: 130°-140 ° C., pressure: 7 mmHg) to obtain 256 mg of 5-chloroisoindoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1.[H][H].C>>[CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1
Reactant: [H][H]
Reactant: Cc1cc(Nc2ccccc2[N+](=O)[O-])cc2c1NC(=O)CC2(C)C
Product: Cc1cc(Nc2ccccc2N)cc2c1NC(=O)CC2(C)C

Procedure:
This compound, m.p. 90°, was prepared similarly to Preparation 17 using 3,4-dihydro-4,4,8-trimethyl-6-[(N-2-nitrophenyl)-amino]-2-(1H)-quinolone hydrogen and palladised charcoal as starting materials. The product was characterised spectroscopically and used directly in Example 14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9]C(C)(O)C)[CH:5]=[CH:4][C:3]=1[CH3:14].[OH-].[Na+].C1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1ccc(C#CC(C)(C)O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: C#Cc1ccc(C)c(F)c1
Yield: 40 %

Procedure:
The mixture of 2-fluoro-4-(3-methyl-3-hydroxy-1-butynyl)toluene (0.035 mol), sodium hydroxide (0.07 mol), and benzene 40 ml was refluxed for 3 hours. After cooling, water 40 ml was added and the mixture was thoroughly stirred. Insoluble materials were filtered away with Celite (trade name of Johns-Manville Company), and the residue was dried over anhydrous magnesium sulfate. The drying agent was separated away, the solvent was carefully distilled away from the solution under reduced pressure, the residue was purified by silica gel chromatography (elution liquid: hexane) and then distilled away the solvent under reduced pressure (boiling point: 100° C., 20 mmHg) to obtain cororless oily 2-fluoro-4-ethynyltoluene (0.014 mol).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:27]([CH3:26])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(Methyl-phenethyl-amino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and N-methylphenethylamine. Mass spectrum (ES) MH+=455.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH3:28]>>[CH2:27]([N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[CH3:28]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 78 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and ethyl bromide, to give the desired product as white solid (78%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:10]([C:19](OCC)=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(-c3ccc(OC)cc3)nc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
To a stirred solution of ethyl 1-ethyl-6-(4-methoxyphenyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (88 mg) in DCM (3 ml) was added 1N diisobutylaluminum hydride in toluene (0.63 ml) at −78° C. and the reaction mixtrue was stirred at −78° C. for 1.5 hours. Another 1N diisobutylaluminum hydride in toluene (0.31 ml) was added at −78° C. and the reaction mxitrue was stirred at −78° C. for 2.5 hours. The reaction mixture was quenched with brine, filtrated through celite pad, and the filtrate was concentrated in vacuo. The residue-was purified by preparative thin layer chromatography eluting with a mixture of CHCl3 and MeOH (9:1) to give [1-ethyl-6-(4-methoxyphenyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (21 mg) as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[C:9]([Br:24])[C:8]1=[O:25].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>ClCCl>[Br:24][C:9]1[C:8](=[O:25])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH:28]=[CH:27][CH:26]=2)[CH2:2][NH:1][C:36](=[O:37])[O:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)[C:12]([CH3:13])=[CH:11][C:10]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CN)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (EXAMPLE 161) (2.00 g, 4.45 mmol) was suspended in dichloromethane (15 mL). Pyridine was added (0.43 mL, 5.34 mmol). After stirring for 10 minutes at room temperature, a stock solution of 4-nitrophenyl chloroformate (10.0 mL, 0.50 M) in dichloromethane was added dropwise. After stirring for 4.5 hours at room temperature, a stock solution of 4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane was again added dropwise and stirring continued at 40° C. overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford a yellow solid (1.11 g, 66%). 1H NMR (400 MHz, DMSO d6) δ 8.56 (app t, J=6.10 Hz, 1H), 8.24-8.21 (m, 2H), 7.62 (app q, J=7.88 Hz, 1H), 7.40-7.27 (m, 7H), 6.98 (d, J=7.52 Hz, 1H), 6.54 (s, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 4.25 (d, J=6.18 Hz, 2H), 2.30 (s, 3H). ES-HRMS m/z 614.0753 (M+H C28H22BrF2N3O6 requires 614.0733).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH:12]1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[N:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH:12]1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1CC(=NCc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 130.4 %

Procedure:
To a solution of 2-Methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (1.00 g, 3.39 mmol), triethylamine (3.77 mL, 27.1 mmol) in dichloromethane (10 ml), cooled at 0° C. in an ice/sodium chloride bath, a solution of titanium tetrachloride in toluene (3.39 mL, 1.0 M in toluene) was dropwise added for 10 minutes. Benzyl amine (0.74 mL, 3.39 mmol) was added and the mixture was stirred over night at room temperature. The reaction was quenched with saturated NaHCO3 solution (100 mL) and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated to give a reddish oil (1.70 g) which was used directly in the next step.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@@H:11]([OH:12])[CH2:10][CH2:9][NH:8]2)=O)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O.[OH-].[Na+]>[CH:1]1([NH:4][CH2:5][C@@H:7]2[C@@H:11]([OH:12])[CH2:10][CH2:9][NH:8]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@H]1NCC[C@@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O[C@H]1CCN[C@@H]1CNC1CC1
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
A mixture of (2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide (3.5 g, 20 mmol) and LAH (2.3 g, 3 eq.) in THF (50 mL) was heated to reflux for 2 hours. The cooled reaction was diluted with water (2.3 mL), a few drops of 10% NaOH, then water (2.3 mL). After stirring for 30 mins, the insolubles were filtered off, the filtrate was concentrated to give 0.8 g of (2R,3S)-2-cyclopropylaminomethyl-pyrrolidin-3-ol as a pale yellow oil. MS m/z 157 [M++1].
Reaction SMILES: C1([Li])C=CC=CC=1.[CH2:8]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1)[CH2:9][CH2:10][CH3:11].[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1)[CH3:20]>C1CCCCC1.C(OCC)C.C(OCC)C>[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][N:16]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccc(CCl)cc1
Reactant: CCCCc1ccc(C)nc1
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCCCc1ccc(CCc2ccc(OCC)cc2)nc1
Reaction time: 1 h

Procedure:
46 ml of a 2.2 molar solution of phenyllithium in cyclohexane/diethyl ether (7:3) are added with ice cooling to a solution of 14.9 g of 5-butyl-2-picoline in 50 ml of diethyl ether. After 1 hour of stirring, 15.9 g of 4-ethoxybenzyl chloride in 50 ml of diethyl ether are then added at room temperature, and the ether starts to boil. The reaction mixture is poured onto ice after 1 hour, and the organic phase is worked up. Separation by column chromatography (silica gel, toluene) and recrystallization gives 2-(p-ethoxyphenylethyl)-5-butylpyridine.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[CH2:24][CH2:23][C:22](=[O:25])[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:44][Sn:45]([CH3:48])([CH3:47])[CH3:46].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Si:1]([O:18][CH2:19][C@@H:20]1[N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:22](=[O:25])[CH:23]([CH2:44][Sn:45]([CH3:48])([CH3:47])[CH3:46])[CH2:24]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C[Sn](C)(C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)C(C[Sn](C)(C)C)C[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-oxopyrrolidine-1-carboxylate (D29) (6 g, 13.23 mmol) in THF (80 ml) cooled at −70° C., LiHMDS 1M solution in THF (17.2 ml) was added dropwise over a period of minutes. The reaction was kept at −78° C. for 1 h before adding (iodomethyl)trimethylstannane (6.04 g, 19.84 mmol) over a period of 5 minutes. The mixture was allowed to warm at −35 and stirred at this temperature for 2 hrs. NH4Cl sat. sol (15 ml) was added and the mixture diluted with EtOAc (40 ml). The organic layer was separated and the aqueous phase acidified to pH˜4 with 0.5N HCl and the latter re-extracted with EtOAc (3×50 ml). The organic phases were combined, dried over Na2SO4 and evaporated in vacuo. The residue was purified by Biotage SNAP-Si (50 g) eluting with a mixture cHex/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D30) as diastereoisomer mixture (3.2 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: Oc1ccnc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2ccccc12
Temperature: 90 °C
Yield: 89 %

Procedure:
POCl3 (50 ml) was added to quinolin-4-ol (5.0 g, 34.9 mmol) and the mixture was heated at 90° C. for 0.5 h. After cooling, the mixture was concentrated in vacuo. The residue was quenched with cold sat. NaHCO3 solution under cooling and the resulting aqueous phase was extracted with chloroform. The combined organic phases were washed with water, dried (Na2SO4) and concentrated in vacuo to give the title compound (5.0 g, 89%) which was used in the next step without further purification.