Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH:30]OS([O-])=O.[K+]>CO.O>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12](=[O:30])[CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(OCc3ccccc3)cc2)C1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCN1CCS(=O)C(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(4-benzyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (0.85 g; 1.77 mmol) in MeOH (25 mL) was added dropwise a solution of Oxone® (0.54 g; 0.89 mmol) in water (25 mL), at 0° C. The resulting mixture was stirred for 2 hours at 0° C., and subsequently, overnight at RT. The resulting mixture was treated with water and a 25% aqueous solution of NH4OH, and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 97.5:2.5) to afford 3-[2-(4-benzyloxy-phenyl)-1-oxo-thiomorpholin-4-yl]-propionic acid tert-butyl ester (0.65 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Fc1ccccc1C1CCCN1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccccc1F

Procedure:
The title compound, white solid, m.p. 108° C. and MS: m/e=324.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([F:16])=[CH:9][C:8]=2[Br:17])=[O:4].[C:18]([O-])([O-])=O.[K+].[K+].CI.O>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:18])[C:12]2[C:7](=[C:8]([Br:17])[CH:9]=[C:10]([F:16])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(=O)c2cc(F)cc(Br)c2[nH]1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)c1cc(OC)c2cc(F)cc(Br)c2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Alternatively, into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 350 mg (1.17 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid methyl ester and 242 mg (1.75 mmol, 1.5 equiv.) of K2CO3. This material is suspended in 20 mL of DMSO then heated to 70° C. for 1 hr. The anion formation of the anion is apparent when the mixture becomes cloudy. The mixture is allowed to cool to 35° C. then 331 mg, 145 μL (2.33 mmol, 2.0 equiv.) of methyl iodide are added and stirring is continued for 2 hr. At the end of this time it is determined if the reaction is complete by LC/MS. Upon completion the mixture is poured into 200 mL of water and the solids which form are collected by filtration and washed with water to give 340 mg (93%) of the O-methylated product after drying.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:45]
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(F)ccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3F)sc2N)c1N1CC[C@@H](F)[C@@H](N)CC1

Procedure:
Following the procedure for Example 221 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2,5-difluorophenyl)thiazole-4-carboxylic acid gave 295 as a dark cream solid (166 mg, 73% over three steps. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.87-7.81 (m, 2H), 7.17-7.09 (m, 1H), 7.07-7.01 (m, 1H), 6.16 (s, 2H), 4.90 (dd, J=47.1, 6.7 Hz, 1H), 3.74 (s, 3H), 3.49-3.32 (m, 3H), 3.23-3.09 (m, 2H), 2.36-2.28 (m, 1H), 2.18-1.81 (m, 3H). Alkyl NH2 not seen. LCMS (ES+) m/z 466 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:10]1.O.NN.O>C(O)C>[NH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13]1
Reactant: COc1ccccc1N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccccc1N1CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(2-methoxyphenyl)-4-[(2-phthalimido)-ethyl] piperazine (23.4 mmol) in 160 mL of ethanol were added hydrazine hydrate (31 mL) and water (40 mL) The mixture was stirred at room temperature for 18 hours. The volatiles were evaporated. The residue was partitioned between ethyl acetate and saturated potassium carbonate solution. The organic layer was washed with brine and water, dried over magnesium sulfate, filtered and concentrated to give 4-[(2-amino)ethyl]-1-(2-methoxyphenyl)piperazine (5.45 g, 99%).
Reaction SMILES: [O:1]=[C:2]([CH3:18])[CH2:3][C:4]([O:6][C@@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([Cl:11])([Cl:10])[Cl:9])=[O:5].[Cl:19][C:20]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>C1C=CC=CC=1.C(O)(=O)CCCCC.N1CCCCC1>[Cl:19][C:20]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:3]([C:2](=[O:1])[CH3:18])[C:4]([O:6][C@@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([Cl:9])([Cl:10])[Cl:11])=[O:5]
Reactant: CC(=O)CC(=O)O[C@@H](c1ccccc1)C(Cl)(Cl)Cl
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CCCCCC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)O[C@@H](c1ccccc1)C(Cl)(Cl)Cl

Procedure:
(S)-2,2,2-Trichloro-1-phenylethyl 3-oxobutanoate (8.6 g 27.5 mmoles) and 2,3-dichlorobenzaldehyde (4.82 g, 27.5 mmoles) in dry benzene (100 ml) were heated at reflux for 5 hours with hexanoic acid (25 drops) and piperidine (8 drops) in a Dean and Stark apparatus. The solvent was evaporated and the residue dissolved in ethyl acetate (200 ml), washed with saturated sodium bicarbonate, 2% aqueous sodium bisulphite solution and brine, dried (MgSO4) and the solvent removed in vacuo. The sub-title compound was obtained as a yellow oil. HPLC and nmr indicate 2:1 mixture of geometric isomers.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:27][CH2:26][C:13]3([C:18]4=[CH:19][CH:20]=[CH:21][N:17]4[C:16]4[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=4[O:14]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:28]([CH3:31])(=[O:30])=[O:29].[CH3:32][OH:33].[H-].[Na+]>CN(C=O)C>[CH3:32][O:33][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:27][CH2:26][C:13]3([O:14][C:15]4[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=4[N:17]4[CH:21]=[CH:20][CH:19]=[C:18]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: CO
Reactant: CS(=O)(=O)c1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1S(C)(=O)=O
Reaction time: 0.17 h

Procedure:
(4-Fluoro-3-methylsulfonyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone (44 mg, 0.10 mmol) and MeOH (12 μL, 0.30 mmol) were combined in DMF (1 mL). NaH (60%, 12 mg, 0.30 mmol) was added and the reaction mixture was stirred for 10 minutes. The mixture was filtered and was purified by reverse phase preparative liquid chromatography utilizing a gradient of 10-99% acetonitrile in water containing 5 mM hydrochloric acid to give (4-methoxy-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 452.1. found 453.5 (M+1)+; Retention time: 1.78 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.87 (d, J=2.0 Hz, 1H), 7.86-7.81 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.22-7.02 (m, 3H), 6.28 (t, J=3.1 Hz, 1H), 6.16 (d, J=2.3 Hz, 1H), 4.52-4.18 (m, 1H), 4.00 (s, 3H), 3.58 (s, 3H), 3.28 (s, 3H), 1.98 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
7-(3-Chloro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (120 mg, 0.26 mmol) and CuCN (47 mg, 0.53 mmol) were suspended in DMF (1.1 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 62 mg. MS: (−) m/z 353.25 (M−1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH2:10][C:11]#[N:12])=[CH:8][C:7]([F:13])=[CH:6][N:5]=1.Br[CH2:15][CH2:16]Cl>CN(C)C=O>[Cl:3][C:4]1[C:9]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15]2)=[CH:8][C:7]([F:13])=[CH:6][N:5]=1
Reactant: ClCCBr
Reactant: N#CCc1cc(F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cc(F)cnc2Cl)CC1
Temperature: 50 °C
Yield: 60.7 %

Procedure:
Sodium hydride (60% in oil, 0.620 g, 15.5 mmol) was washed with hexanes (2×10 mL) under nitrogen. Dry dimethylformamide (5 mL) was added and the suspension cooled in an acetone/ice bath. A solution of 2-(2-chloro-5-fluoropyridin-3-yl)acetonitrile (0.571 g, 3.35 mmol) in dry dimethylformamide (10 mL) was added slowly and the reaction stirred for minutes. 1-Bromo-2-chloroethane (0.300 ml, 3.60 mmol) was added. After stirring in the cold bath for 5 minutes, the orange mixture was removed from the cold bath and heated at 50° C. After 45 minutes the mixture was cooled and carefully quenched by addition of saturated ammonium chloride (10 mL) then partitioned between 10% saturated ammonium chloride (200 mL) and ethyl acetate (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified using silica chromatography (hexane to ethyl acetate gradient) to give the desired 1-(2-chloro-5-fluoropyridin-3-yl)cyclopropanecarbonitrile (0.400 g, 2.034 mmol, 60.8% yield).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].N1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>ClCCl>[CH2:4]=[CH:3][CH2:2][CH2:1][O:5][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCO
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 94.2 %

Procedure:
In a reactor 3-buten-1-ol (33.2 g) and pyridine (230 ml) were charged and p-toluene sulfonyl chloride (96.7 g) was added thereto over 3.5 hours, while maintaining the internal temperature not higher than 5° C. under cooling in an ice bath. After stirring for 30 minutes, the reaction mixture was added to water (250 ml). Dichloromethane (250 ml) was added thereto and subjected to liquid separation. A saturated aqueous sodium carbonate solution (250 ml) and water (200 ml) were added to wash the lower layer, followed by liquid separation and washing with water (200 ml) twice, and dried over magnesium sulfate. After filtration followed by distillation to remove the solvent, 98.1 g of CH2═CH(CH2)2OTs was obtained.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[C:11]([OH:18])=[CH:10][C:7]=1[C:8]#[N:9])=[O:5].O1CCCC1.[C:28](Cl)(=[O:32])[O:29][CH2:30][CH3:31].C(N(CC)CC)C.[C:41]([O:44][CH2:45][CH3:46])(=[O:43])C>>[CH2:30]([O:29][C:28]([O:17][C:12]1[C:11]([O:18][C:41]([O:44][CH2:45][CH3:46])=[O:43])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:4](=[O:5])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[F:1])[C:13]=1[N+:14]([O-:16])=[O:15])=[O:32])[CH3:31]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1F
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc(C#N)c(C(=O)c2ccccc2F)c([N+](=O)[O-])c1OC(=O)OCC
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-fluorobenzoyl)-4,5-dihydroxy-3-nitrobenzonitrile (compound 1-29) (70 mg) and tetrahydrofuran (2.0 mL) were added ethyl chlorocarbonate (70 μl) and triethylamine (110 μl) under ice-bath cooling. After stirring for 30 minutes, the mixture was stirred at room temperature for 2 days. The mixture was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-30% ethyl acetate/hexane, gradient elution) to give the title compound (103 mg). The structural formula was illustrated in table 10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.[I:40]I>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][C:10]=1[I:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)cc1
Reactant: II
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 88 h
Yield: 158.2 %

Procedure:
A solution of 4-(benzyloxy)benzotrifluoride (12.71 g, 50.4 mmol) in acetonitrile (300 ml) was stirred under nitrogen and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (17.75 g, 50.4 mmol) and iodine (6.4 g, 25.2 mmol) added. The mixture was stirred at room temperature for 88 h. The solvent was evaporated and the residue partitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was washed with water, dried (MgSO4) and evaporated to an orange oil which was purified by flash chromatography (silica gel, 5% ethyl acetate: isohexane) to give the title compound as an orange oil (15.07 g, 79%)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.[Li+].[CH3:24]C([N-]C(C)C)C.CI>C1COCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:13][CH2:14][C:15]([CH3:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A solution of ii (0.30 g, 1.0 mmol) in THF (10 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.60 M in THF, 1.88 mL, 3.0 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min followed by addition of methyl iodide (0.311 mL, 5.0 mmol) at −78° C. The temperature of the reaction mass was slowly raised up to RT and left to stir overnight. The reaction was cooled to 0° C. and quenched by dropwise addition of saturated NH4Cl solution (30 mL). The reaction was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to obtain iii (0.30 g, 97%). MS 316.12 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25](#[N:27])C>>[N:5]1([CH2:4][CH2:3][CH2:2][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][C:25]#[N:27])=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC#N
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCc1ccc(OCCCN2CCCC2)cc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A mixture of 1-(3-chloropropyl)pyrrolidine (J. Am. Chem. Soc., 77, 2270; 1955) (133 g, 0.9 mol), 4-hydroxybenzonitrile (100 g, 0.75 mol) and caesium carbonate (256 g, 0.78 mol) in acetonitrile (1 L) was stirred at 45° C. for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (800 mL) and water (800 mL). The aqueous layer was separated and extracted with ethyl acetate (800 mL) and the combined organic solution was washed with water (500 mL) and extracted with 2M hydrochloric acid (2×600 mL). The acidic solution was basified to pH8-9 with 40% potassium hydroxide solution and extracted with ethyl acetate (800 mL). The aqueous solution was then further basified to pH10-11 using 40% potassium hydroxide solution and extracted with ethyl acetate (800 mL). The combined organic solution was dried over sodium sulfate, filtered through a pad of silica and concentrated in vacuo to afford the title compound as a red oil in 79% yield, 150 g. 1H NMR (400 MHz, CDCl3) δ: 7.24 (2H, d), 6.85 (2H, d), 4.09-3.89 (2H, m), 3.75 (2H, s), 2.71-2.36 (6H, m), 2.14-1.93 (2H, m), 1.89-1.65 (4H, m) ppm; LRMS APCI m/z 245 [M+H]+
Reaction SMILES: [O:1]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:8]([OH:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].CCN(CC)CC.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([O:1][C:23](=[O:25])[CH3:24])[P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])[CH3:7]
Reactant: CCOP(O)OCC
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OC(C)=O)P(=O)(OCC)OCC
Temperature: 0 °C
Yield: 50.9 %

Procedure:
Ethyl 2-oxoacetate (50%) (74 g, 724.8 mmol, 1.0 eq.) was added dropwise with stirring at 0° C. to a solution of diethyl hydrogen phosphite (50 g, 362.1 mmol, 1.0 eq.) in toluene (100 mL), under nitrogen. Et3N (110 g, 1.1 mol, 3.0 eq.) was added dropwise with stirring at 0° C. The resulting solution was stirred for 1 hour at room temperature. To the mixture was added acetic anhydride (37 g, 362.4 mmol, 1.0 eq.) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 6 with 2N HCl. The resulting solution was extracted with DCM (3×150 mL) and the organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The residue was loaded onto a silica gel column with EtOAc:hexanes (1:2˜1:5) to yield the title compound (52 g) as a light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.N1C=CC=CC=1.[C:37]1(=[O:53])[N:41]([CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45])[C:40](=[O:48])[C:39]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:38]12>C(Cl)Cl.O>[C:40]1(=[O:48])[N:41]([CH2:42][CH2:43][S:44]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]4[C:25]([NH:26][CH:27]([CH3:28])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:15][CH2:14]2)=[O:12])=[CH:5]3)(=[O:45])=[O:46])[C:37](=[O:53])[C:38]2=[CH:52][CH:51]=[CH:50][CH:49]=[C:39]12
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN4C(=O)c5ccccc5C4=O)ccc3[nH]2)CC1
Reaction time: 72 h

Procedure:
To a solution of 1-[5-aminoindole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (PREPARATION 56, 606 mg) in dry methylene chloride (5 ml) under nitrogen is added pyridine (127 μl, 1.05 equivalents) and 2-phthalimidoethanesulfonyl chloride (400 mg). The mixture is stirred at 20°-25° for 3 days and then diluted with methylene chloride (40 ml) and water (20 ml). The layers are separated and the organic phase is washed with saline (15 ml), dried over sodium sulfate, and concentrated under reduced pressure to give a residue which is then chromatographed on silica gel (230-400 mesh, 85 g, 8 psi), eluting with a gradient of methanol/chloroform (1/99-2.5/97.5). The appropriate fractions (Rf =0.33, TLC, methanol/chloroform, 5/95) are pooled and concentrated to give the title compound, NMR (CDCl3) 10.33, 7.80, 7.76-7.63, 7.35, 7.22, 6.95, 6.85, 6.69, 4.65, 4.51, 4.13, 3.60-3.40, 3.40-2.90, 2.64, 1.94, 1.65 and 1.22 δ.
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][C@H:7]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+:4]=[N-:5].[CH3:25]I>CN(C=O)C>[N:3]([CH2:6][C@H:7]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[N+:4]=[N-:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN=[N+]=[N-])COCc1ccccc1
Reaction time: 0.5 h
Yield: 114.7 %

Procedure:
To a solution NaH (0.29 g, 7.35 mmol) in DMF (10 mL) was added a solution of (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-ylcarbamate (1.5 g, 4.9 mmol) in DMF (10.0 mL). The mixture was stirred for 30 min. MeI (1.0 mL, 9.8 mmol) was then added. The mixture was stirred for another 2 h. LCMS indicated the completion of the reaction. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (200 mL×2). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-yl(methyl)carbamate (1.8 g), which was used without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:14])([CH3:13])[CH:7]=[C:6]2[CH3:15])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[CH:12][CH:11]=2)[CH:6]([CH3:15])[CH2:7][C:8]1([CH3:14])[CH3:13])(=[O:18])[CH3:17]
Reactant: CCc1ccc2c(c1)C(C)=CC(C)(C)N2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCc1ccc2c(c1)C(C)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1,2-dihydro-6-ethyl-2,2,4-trimethylquinoline (800 mg) with acetyl chloride (3.5 ml) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (25 ml) was performed according to the method described in example 37.