Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
t-Butyl-piperidin-4-ylcarbamate (3 g, 15 mmol) obtained in Preparation Example 2-ii was dissolved in methanol (30 ml) in a 100 ml vessel, and acetone (7.70 ml, 105 mmol) and acetic acid (0.45 ml, 7.5 mmol) were added thereto while stirring. To the resulting mixture, NaCNBH3 (1.88 mg, 30 mmol) was added dropwise in 4-divided portions and reacted for 18 hrs. After the completion of reaction, ice water was poured to the reaction product while stirring, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 2.644 g of the title compound as a white solid (yield 73.3%).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]1.[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:13]12([CH2:23][C:24]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[CH:3]3)=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1cnc2ccccc2c1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.8 %

Procedure:
3-Amino-4(3H)-quinazolinone (158.7 mg, 0.99 mmol) was dissolved in chloroform (5 mL). 1-Adamantaneacetyl chloride (204.1 mg, 0.96 mmol) and pyridine (100 μL, 1.24 mmol) were added, and the reaction was allowed to stir at ambient temperature for 22 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white solid (264.9 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.69 (m, 12H), 1.96 (br s, 3H), 7.58-7.63 (m, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.87-7.93 (m, 1H), 8.18-8.20 (m, 2H), 11.12 (s, 1H) ppm; MS (DCI/NH3) m/z 338 (M+H)+; Elemental Analysis: Calculated for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.11; H, 6.85; N, 12.43.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:23])[NH:18]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][CH:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:23])[N:18]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCC(Br)Br
Reactant: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2n1CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.093 g, 6.45 mmole) in DMF (10 mL), (2-methyl-1H-indol-4-yloxy)-acetic acid benzyl ester (2) (0.845 g, 2.3 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture, dibromododecane (0.765 g, 2.3 mmole) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was separated, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (10:1, hexane: EtOAc) to afford intermediate 3. Yield: 0.708 g, 45%.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[C@H:27]([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:20]1[CH3:29])=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[C@H:27]([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:20]1[CH3:29])=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)[C@H](C)c2ccccc2[C@@H]1C
Reactant: O=C(O)c1cccc2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)[C@H](C)c2ccccc2[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), (cis)-2-Amino-1,3-dimethyl-indan-2-carboxylic acid ethyl ester (636 mg, 2.72 mmol), HATU (1.3 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 50-50% EtOAc in heptane) to give a pure product (76) as white solid (79 mg, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: CCCNC
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Yield: 78.3 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3.1 g) in anhydrous dimethylformamide (70 cc), N,'-carbonyldiimidazole (1.4 g) and N-methylpropylamine (0.6 g). After recrystallization in ethanol, [2-(7-methoxy-1,8-naphthyridin-2yl)-3-oxo1 -isoindolinyloxy]-N-methyl-N-propylacetamide (2.7 g), m.p. 160° C., is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:6]OC)[C:3]([NH2:5])=[O:4].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N.N.[OH-].[Na+]>>[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH:5][C:3](=[O:4])[C:2]([CH3:6])=[CH2:1]
Reactant: COCC(C)C(N)=O
Reactant: CN(C)CCCN
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)C(=O)NCCCN(C)C

Procedure:
117.2 g (1.0 mole) of 2-methyl-3-methoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 20 hours in a temperature range of 145°-175° C. until the evolution of ammonia is complete. The mixture is allowed to cool, 1.5 g of sodium hydroxide is added and the mixture is heated in a high vacuum at 90° to 110° C. The methanol is split off within about 30 minutes, vigorous foaming occurring. The temperature is increased and 122 g (0.72 mole=72% of the theoretical yield) of colorless oil having a Bp0.1 of 106°-110° C. are distilled off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)NS(C)(=O)=O)C1

Procedure:
Compound 755 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and methane sulfonamide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30%–40% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0158 g, 13% yield). HRMS (M−H) calcd for C18H20N3Cl2O6S: 476.04499; found: 476.0431.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:1]([C:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)(C)C1(O)CCCCC1

Procedure:
According to Example 2, t-BuMgCl.LiCl (1.01 M in THF 2.18 mL; 2.20 mmol; 1.10 equiv) was reacted with cyclohexanone (178 mg; 2.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv). Column chromatographical purification (silica; pentane:Et2O, 9:1) afforded the desired product as colorless oil, which started to crystallize after being chilled, mp=49−50° C. (287 mg, 92%).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(4-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (63.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 7.85, 7.48-7.46, 7.41-7.32, 7.02, 4.08-4.05, 3.95-3.88, 3.80-3.68, 3.52-3.45, 3.35, 1.73-1.68, 1.51, 0.94.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][C@@H:29]([OH:32])[C:30]#[CH:31]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:31]#[C:30][C@H:29]([OH:32])[CH3:28])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Reactant: C#C[C@@H](C)O
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 23.2 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (70 mg, 0.142 mmol), palladiumbisdichlorobistriphenylphosphine (9.96 mg, 0.014 mmol), copper(I) iodide (1.351 mg, 7.09 μmol) and TEA (0.099 ml, 0.710 mmol) in THF (6 ml) was added (2R)-3-butyn-2-ol (24.85 mg, 0.355 mmol) and the reaction mixture was irradiated in a personal microwave reaction for 10 minutes at 120° C. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(3R)-3-hydroxy-1-butyn-1-yl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (16 mg, 0.033 mmol, 23% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.24-7.45 (m, 3H), 7.11 (s, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 4.47-4.70 (m, 3H), 1.41 (d, 3H). LC-MS (ES+) m/z 482.03, [M+H].
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[H-].[Na+].CI.[C:38](OCC)(=O)C>O1CCCC1>[CH3:38][N:15]([C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:30])([F:29])[F:31])[CH:22]=1)[C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3cccc(OC(F)(F)F)c3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)CCC#Cc1cccc(OC(F)(F)F)c1)c1ccc2ccn(CC(=O)O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
{6-[5-(3-Trifluoromethoxy-phenyl)-pent-4-ynoylamino]-indol-1-yl}-acetic acid ethyl ester (50 mg, 0.11 mmol) was added to a suspension of sodium hydride (9 mg, 0.22 mmol) in tetrahydrofuran (1.5 ml) at 0° C. The mixture was stirred for 30 min at 0° C., methyl iodide (30 μl, 0.44 mmol) was added and stirring was continued for 14 h at ambient temperature. The suspension was cooled to 0° C., sodium hydride (13 mg, 0.33 mmol) and methyl iodide (45 μl, 0.66 mmol) were added and the mixture was stirred for 4 h at ambient temperature. Ethyl acetate was added, the solution was successively washed with brine, 1 N HCl/ice water 1/1 and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 42 mg (0.09 mmol, 82%) of the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[Si]([O:21][CH2:22][C@@H:23](/[N:28]=[CH:29]/[C:30]([F:33])([F:32])[F:31])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C)C.[NH4+].[Cl-]>CCOCC>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C@H:29]([NH:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:21])[C:30]([F:32])([F:31])[F:33])=[CH:3][CH:4]=1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F
Reactant: Clc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloropyridine (2.5 g, 13 mmol) in ether (30 mL) at −78° C. was added n-butyllithium (13 mmol, 2.5 M in hexane). The mixture was stirred at −78° C. for 1 h. (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine (3.64 g, 11.7 mmol, see Step 2, Example 8) was added. The mixture was stirred at −78° C. for 2 h. Saturated aqueous NH4Cl was added to the reaction mixture and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil (5.3 g). The crude oil (2.0 g) was then treated with (Bu)4NF (6 mL, 1M in THF). The mixture was stirred at rt for 1 h, saturated aqueous NH4Cl was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil. Chromatography (20% EtOAc/hexane) afforded the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][S:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14]
Reactant: CC(C)(N)CN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(N)CNS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 14.97 g (0.196 mol) of 1,2-diamino-2-methylpropane in 300 ml of chloroform and 80 ml pyridine at 0° C. was added 10 g (0.057 mol) of benzenesulfonyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to reach room temperature. The mixture was evaporated to dryness in vacuo and the residue was partitioned between water and chloroform. Evaporation of the chloroform gave 10.3 g (79%) of semisolid. The product was identified by NMR and IR spectroscopy and elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([F:11])[S:7]1(=[O:13])=[O:12].C([Li])CCC.[F:25]NS(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([F:25])([F:11])[S:7]1(=[O:13])=[O:12]
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: COc1ccc(CN2CCC(F)S2(=O)=O)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCC(F)(F)S2(=O)=O)c(OC)c1
Reaction time: 1 h
Yield: 1.8 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-5-fluoroisothiazolidine-1,1-dioxide (5.700 g, 19.7 mmol) in anhydrous tetrahydrofuran (225 mL), cooled to −78° C., was slowly added n-butyl lithium (14.973 mL of a 2.5 N solution in hexanes, 37.4 mmol) and the resulting dark orange/red solution stirred for 1 hr. A solution of N-fluorobenzene sulfonamide (14.6 g, 46.3 mmol) in anhydrous tetrahydrofuran (60 mL) was added slowly over 30 mins, stirring at −78° C. for 3 hrs and at room temperature for 2.5 hrs. The reaction was poured into saturated aqueous ammonium chloride, diluted with ethyl acetate, and the organic layer isolated. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was suspended in methylene chloride and filtered through a pad of silica gel, washing with methylene chloride, and concentrating the solution. The crude material was purified by silica gel chromatography (20-75% ethyl acetate/hexanes) and then by preparative HPLC (C18, 32-95% acetonitrile/water over 17 mins) to give a tan oil (0.106 g, 2%). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.18 (d, 1H, J=8.4 Hz), 6.49-6.45 (m, 2H), 4.28 (s, 2H), 3.82 (s, 3H), 3.14 (s, 3H), 3.19-3.15 (m, 2H), 2.70-2.55 (m, 2H).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Br)=[O:4].Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOC(C)=O>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([NH:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: CCC(Br)C(=O)Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(Br)C(=O)NOCc1ccccc1
Yield: 72 %

Procedure:
Prepared in 72% yield (4.71 g, 17.3 mmol) from the reaction of 2-bromobutyryl bromide (5.0 g, 24 mmol) with O-benzylhydroxylamine, hydrochloride via general procedure A. Rf=0.49 (3:1, hexanes:EtOAc); mp=99.3-101.6° C.; 1H-NMR (500 MHz, CDCl3): δ 8.92 (br s, 1H), 7.52-7.31 (m, 5H), 4.93 (s, 2H), 4.12 (app q, J=7.2 Hz 1H), 2.02-1.94 (m, 2H), and 1.00 (t, J=7.0 Hz, 3H); 13C-NMR (126 MHz, CDCl3): δ 166.6, 134.8, 129.5, 129.0, 128.7, 78.4, 48.8, 28.8, and 11.8; FT-IR (neat) 3112, 2963, 2933, 2874, 1695, 1668 (s), 1528, 1496, 1454, 1364, 1177, 1089, 1023 cm-1. HRMS calculated for C11H15BrNO [M+H]+, 256.0332; found 256.0329.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:20][N:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc([N+](=O)[O-])ccc1N(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of N-(2-methyl-4-nitrophenyl)benzamide (Example 1099A) (0.38 g, 1.48 mmol) in DMF (2 mL) was added cesium carbonate (1.2 g, 3.68 mmol) followed by methyl iodide (0.12 mL, 1.9 mmol). The reaction mixture was stirred at room temp for 2 hr, extracted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give N-methyl-N-(2-methyl-4-nitrophenyl)-benzamide (0.38 g, 95%). ES-MS (M+H)+=271.
Reaction SMILES: C1([Se][Cl:8])C=CC=CC=1.[CH2:9]([C:12]1([NH2:27])[CH2:16][CH2:15][C@@H:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13]1)[CH:10]=[CH2:11]>C(#N)C>[Cl:8][CH:10]1[CH2:9][C:12]2([CH2:16][CH2:15][C@@H:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)[NH:27][CH2:11]1
Reactant: Cl[Se]c1ccccc1
Reactant: C=CCC1(N)CC[C@@H](C(=O)OCc2ccccc2)C1
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@H]1CCC2(CC(Cl)CN2)C1
Temperature: 80 °C

Procedure:
To phenylselenyl chloride (0.199 g, 1.041 mmol) was added (1R)-benzyl 3-allyl-3-aminocyclopentanecarboxylate (example 2, step A, 0.090 g, 0.347 mmol) dissolved in acetonitrile (2 mL). The contents were heated at 80° C. for 18 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. To the residue was added methanol (5 mL). The solid that separates was filtered and washed with methanol (2 mL). To the filtrate was added 4.0N hydrogen chloride in dioxane (1 mL) and the contents concentrated. Ethyl acetate was added and the resulting mixture was concentrated under reduced pressure. Methanol (5 mL) was added and a solid separates out The liquid was carefully pipetted out into a HPLC vial and subjected to preparative HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the desired product were isolated and concentrated. The residue was partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (3 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield (7R)-benzyl 3-chloro-1-azaspiro[4.4]nonane-7-carboxylate (0.051 g, 0.174 mmol, 50.0% yield) as an oil. It was used as such for the subsequent step. MS (ESI) m/z 294.14 (M+H)+
Reaction SMILES: Cl[C:2]1(F)[C:11]([F:12])=[C:10]2[N:5]([C:6](=[O:20])[CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[C:9]2[CH2:13][CH3:14])[C:4]([F:21])=[C:3]1[F:22].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[CH2:13]([C:9]1[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6](=[O:20])[N:5]2[C:10]=1[C:11]([F:12])=[C:2]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)[C:3]([F:22])=[C:4]2[F:21])[CH3:14]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C1C=C(CC)C2=C(F)C(F)(Cl)C(F)=C(F)N2C1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CC)c2c(F)c(N3CCN(C)CC3)c(F)c(F)n2c1=O
Temperature: 85 °C

Procedure:
Ethyl 8-chloro-1-ethyl-6,7,8,9-tetrafluoro-4H-quinolizin-4-one-3-carboxylate (317 mg, 1.0 mmol), from Step 4, is dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reaction mixture is heated at 85° C. for 2.5 hours. The reaction mixture is allowed to cool to ambient temperature and then concentrated in vacuo in order to remove all of the pyridine. The residue is dissolved in 50 mL of methylene chloride and the methylene chloride solution is washed with 50 mL of 5% aqueous sodium bicarbonate solution. The aqueous layer is extracted with 3×50 mL of methylene chloride and the combined methylene chloride solutions are dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford the title compound.