Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.[NH2:21][C@@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[CH:31]([NH:30][C:28]([C@H:25]1[CH2:24][CH2:23][C@@H:22]([NH:21][C:2]2[CH:3]=[C:4]([O:5][CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH2:27][CH2:26]1)=[O:29])([CH3:33])[CH3:32]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCCC2)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
To a solution of 1-(2-(3-fluoro-4-nitrophenoxy)ethyl)piperidine (220 mg, 0.820 mmol) and cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (190 mg, 0.861 mmol) in ACN (0.8 mL) was added DIPEA (0.301 mL, 1.722 mmol). The mixture was heated at 80° C. in a sealed tube for 14 hours, and then additional cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (38 mg, 0.172 mmol) and DIPEA (0.100 mL, 0.574 mmol) were added. The resulting mixture was heated an additional 24 hours. The mixture was diluted with DCM (5 mL), washed with water/brine mixture, brine, and the organic layer was dried over Na2SO4, filtered and evaporated to afford cis-N-isopropyl-4-(2-nitro-5-(2-(piperidin-1-yl)ethoxy)phenylamino)cyclohexanecarboxamide.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:17](=[O:18])[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:19])[C:8]=2[CH2:7][CH2:6]1)[CH3:3].[I:20][CH3:21]>>[I-:20].[CH3:3][N+:2]([CH3:21])([CH3:1])[CH2:4][CH:5]1[C:17](=[O:18])[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:19])[C:8]=2[CH2:7][CH2:6]1
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Reactant: CI
Product: Cn1c2c(c3ccccc31)C(=O)C(C[N+](C)(C)C)CC2
Product: [I-]

Procedure:
A suspension of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (3.80 g) in iodomethane (100 ml) was stirred at reflux for 57 h. The resulting suspension was concentrated in vacuo to give the title methanaminium iodide as a solid (5.72 g) m.p. 192°-195°.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=1.C([O-])(=O)C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([CH3:17])[CH:10]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C)cc(Br)cc1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Ethyl bromoacetate (0.66 mL) was added to a mixture of 4-bromo-2,6-dimethylphenol (1.0 g) and potassium acetate (1.03 g) in N,N-dimethylformamide (10 mL), and stirred at 80° C. for 3 hrs. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elent: ethyl acetate/n-hexane=1/10) to afford the title compound (1.29 g).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8])C>CO.O.Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[N:9]1[CH:4]=[CH:5][NH:6][C:7]1=[O:8]
Reactant: CCOC(CNC(=O)Nc1ccc(F)cc1F)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]ccn1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.4 %

Procedure:
This urea compound (37.5 g) was dissolved in a mixture of 560 ml of methanol and 280 ml of water, 300 ml of 0.48M hydrochloric acid was added thereto and the mixture was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure and the crystals separated out were washed with a mixture of water and methanol (5:1) to give 22.8 g of 1-(2,4-difluorophenyl)-2-(1H,3H)-imidazolone as a colorless powder.
Reaction SMILES: C(OC)(=O)C1C=CC(C(OC)=O)=CC=1.C(O)CCCO.C[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1N=C=O>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:25]1([N:28]=[C:29]=[O:30])[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: OCCCCO
Product: O=C=Nc1ccccc1
Temperature: 210 °C
Reaction time: 3 h

Procedure:
In a 1 liter three-necked resin flask equipped with nitrogen inlet and outlet, thermometer, condenser and mechanical stirrer, were placed 194 grams (1 moles) of dimethyl terephthalate, 207 grams (2.3 moles) of 1,4-butanediol and 0.173 grams of titanium tetraisopropoxide. The mixture was heated at 210° C. for 2 hours while distilling out methanol. The resulting mixture was heated at 250° C. for 30 minutes, and then vacuum was applied for 3 hours. After vacuum was released and replaced with nitrogen, 2,4-toluenediisocyanate (5.48 grams, 0.0314 moles) was added into the flask. The resulting polymer was stirred for 10 minutes at 250° C., and then was cooled to room temperature to obtain phenyl isocyanate terminated copolyester with an intermediate molecular weight, I.V. 1.98 dL/g as determined at 25° C. and 0.1% concentration in HFIP/PFP 50/50; Tmp 220° C.; heat of fusion 37 j/g; Tg 47° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[CH:4]=[CH:5][N:6]=1
Reactant: O=CN1CCC(CCCBr)CC1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1CCCC1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of 2-methylimidazole (2 g, 0.025M) and sodium hydride (1.2 g, 50% in mineral oil, 0.025M) in dimethylformamide (20 ml) was stirred at room temperature for 1/2 hr. The reaction mixture was then heated at 50° C. and the solution of 4(3-bromopropyl)piperidine carboxaldehyde (4.6 g, 0.02M) in dimethylformamide (20 ml) was added slowly. After completing the addition, the reaction was heated at 50° C. for 4 hrs and then solvent was removed in vacuo. Water (80 ml) was added to the residue and the mixture was extracted with methylene chloride. The combined extracts, dried over sodium sulfate, were stripped to dryness to yield an oil. The oil was purified on silica gel column, eluted with methanol chloroform (1:9 v/v) to give 4-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-1-piperidinecarboxaldehyde (3.86 g, 88% yield).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:29])[CH:12]=[CH:13][CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>O1CCCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21](/[C:15](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: CCCCCC(=CC=CC(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: CCCCC/C(=C\C=C\C(=O)NCCCCc1cccnc1)c1ccc(OC)cc1
Yield: 50.6 %

Procedure:
As in Example 134, a solution of (E,E)]-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester (2.5 g) and 3-pyridinebutanamine (1.12 g) in tetrahydrofuran (25 mL) was stirred overnight at room temperature. After the usual work up, the crude product was purified by HPLC (ethyl acetate) and then was crystallized from ether-hexane to provide 1.3 g of (E,E)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-decadienamide, mp 83.5°-84.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[Br:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Br
Reactant: Brc1ccccn1
Product: Brc1cccc(-c2ccccn2)c1

Procedure:
2-bromophenylboronic acid (35.0 g, 0.174 mol) was reacted with 2-bromopyridine (55.1 g, 0.348 mol) under standard Suzuki coupling condition. The excess 2-bromopyridine was removed via vacuum distillation at 125° C. The product was collected at 180° C. as a light yellow liquid (29 g, 71%) and used for the next reaction without additional purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=O)[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1CCCO1>[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=[CH2:1])[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC1CCCO1
Product: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (2.2 eq.) in 2-methyl tetrahydrofuran (3 vol) was added rapidly solid potassium tert-butoxide (2.3 eq.) maintaining the temperature around 0° C. The temperature was kept at +20° C. for 2 hours (a suspension remained) and re-cooled to 0° C. Keeping the temperature below 6° C., (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (1 eq.) was added over 40 minutes. The reaction was warmed to room temperature and stirred for 16 h and then cooled to 0° C. The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) and the aqueous layer was separated. The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite®. The aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol). The organic phase was dried (MgSO4) and the solvent removed. The crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol). The combined aqueous layers were acidified at ambient temperature with 6 N HCl to pH=3, and extracted twice with ethyl acetate (10 vol, then 8 vol). The combined extracts were dried (Na2SO4), the solvent removed and the crude product was recrystallized from cyclohexane (5 vol) to afford the title compound. 1H-NMR (400 MHz, DMSO): δ 12.9, (broad, 1H); 5.00 (m, 2H); 4.24 (dt, J=1.9H, J=7.3 Hz, 1H), 3.91 (m, 2H); 2.98 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.41 and 1.36 (2 s rotamers, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]([NH2:16])=O)[C:8](=[CH:12][CH:13]=1)[C:9]([NH2:11])=O)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[C:1]([C:5]1[CH:6]=[C:7]([C:14]#[N:16])[C:8](=[CH:12][CH:13]=1)[C:9]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(N)=O)c(C(N)=O)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(C#N)c(C#N)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
4-t-butylphthalonitrile was prepared by fitting a 500 milliliter three-necked flask with a nitrogen inlet, a 100 milliliter pressure equalizing funnel, and a stopper, placing the flask in an ice bath, and charging the flask with 60 grams (0.2713 mole) of 4-t-butylphthalamide and 400 milliliters of pyridine. The resulting mixture was kept under a constant flow of nitrogen. Phosphorus oxychloride (49.7 milliliters, 0.5426 mole) was placed in the dropping funnel and added slowly to the pyridine solution to keep the temperature at about 4° C. The reaction was magnetically stirred for 4 hours and the mixture was then poured into a beaker containing 200 milliliters of crushed ice. Water was added until the total volume was 1,600 milliliters and a light brown solid was produced. The solid was removed by suction filtration, resulting in 31.24 grams (0.1696 mole) of 4-t-butylphthalonitrile, which exhibited a melting point of 58° to 59° C. The identity of the 4-t-butylphthalonitrile product was confirmed by IR spectrum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N+:15]([O-])=[CH:14][C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH3:27])[N:22]3[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:32]=C=O)=O.C(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:32])[C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@@H:23]([CH3:27])[N:22]3[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: C[C@H]1COCc2nc3c[n+]([O-])c4ccc(OCc5ccccc5)cc4c3n21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@@H]1COCc2nc3c(N)nc4ccc(OCc5ccccc5)cc4c3n21
Reaction time: 1 h
Yield: 67 %

Procedure:
(11S)-2-(Benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (2.02 g, 5.59 mmol) and trichloroacetyl isocyanate (0.87 mL, 7.27 mmol) were dissolved in dichloromethane (50 mL) under an atmosphere of N2. After one hour, the reaction was quenched with a small amount of methanol, and the solvent was removed under reduced pressure. The resulting residue was suspended in methanol (50 mL) and treated with NaOMe (25% in MeOH, 8 mL) for 20 hours. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane and water, adjusting to pH 11 with NH4OH. The aqueous layer was extracted with dichloromethane (3×). The combined organic layers were then washed with brine and dried over Na2SO4, filtered, and concentrated to give a light-brown foam. Chromatography (SiO2, 0-20% CMA/CHCl3) gave (11R)-2-(benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (1.35 g) as an off white solid, mp 100-120° C.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:56]=[O:57])C.Cl>C1COCC1.CO>[C:36]1([N:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:9]2[CH:10]=[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][C:2]([CH:56]=[O:57])=[CH:14][C:13]=4[C:12]3([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:7][CH:8]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(C=O)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (7-bromo-9,9-didecylfluoren-2-yl)diphenylamine (34.6 g, 0.05 mol) in THF (200 mL), cooled to less than −50° C., a solution of n-butyllithium in hexanes (1.6M, 45 mL, 0.072 mol) was added over 15 minutes. After 30 minutes, a solution of DMF (7.5 mL, 0.097 mol) in THF (40 mL) was added, and after 1 hour, the temperature was allowed to rise to 0° C. The mixture was cooled in an ice bath, and treated with dilute hydrochloric acid (7.5 mL conc. HCl mixed with 60 mL water). After dilution with toluene (200 mL), the organic phase was washed with water, aqueous sodium bicarbonate, and saturated sodium chloride solution, dried and concentrated. The residue was chromatographed over 500 g of silica gel. Elution with 20% toluene-heptane and after removal of solvent, the product, which was initially obtained as a glassy solid, on standing with methanol (150 mL), crystallized into yellow solids, 28.2 g, (88% yield), m.p. 77-78.5° C. Anal. Calcd. for C46H59NO: C, 86.06%; H, 9.26%; N, 2.18%. Found: C, 85.81%; H, 9.49%; N, 2.10%. 1H NMR (270 MHz; CDCl3, ppm): 0.61-0.65 (broad), 0.83, 0.85, 0.88 (triplet), 1.05-1.29 (complex, broad), 1.80-2.00 (complex multiplet), decyl protons, 20H; 7.02, 7.03, 7.04, 7.05, 7.06, 7.07, 7.12,, 7.15, 7.24, 7.26, 7.29, 7.59, 7.62, 7.69, 7.72, 7.80, 7.82, 7.83 (complex multiplets, aromatic protons, 16H); 10.02 (singlet, CHO proton, 1H). 13C-NMR (CDCl3, noise-decoupled, ppm): 14.11, 22.66, 23.84, 29.11, 29.29, 29.55, 29.92,31.88, 40.03, 55.15 (sp3 carbons); 118.21, 119.11, 121.70, 122.82, 123.11, 123.31, 124.38, 129.30, 130.83, 134.02, 134.51, 147.49, 147.64, 148.85, 151.30, 153.69 (sp2 carbons); 192.19 (sp2 carbon of CHO moiety).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CCOC(C)=O.CCCCCC>[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:16](=[O:18])[CH3:17])[CH:10]=1
Reactant: CC(=O)Nc1cc(Br)ccn1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(C)=O)c2cc(Br)ccn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a 20 mL vial charged with Sodium hydride (0.196 g, 7.76 mmol) was added dry N,N-Dimethylformamide (5.0 mL, 64 mmol), cooled with ice bath. N-(4-bromopyridin-2-yl)acetamide (1.50 g, 7.00 mmol) was added portionwise in ˜3 min. The suspension was stirred at the same temperature for 15 min and turned into a clear solution. 4-methoxybenzyl bromide (1.55 g, 7.70 mmol) was added dropwise with a syringe and rinsed down with dry N,N-Dimethylformamide (2.0 mL, 26 mmol). The mixture was stirred at r.t. for 17 hours. The mixture was poured into ice chilled saturated NaHCO3 (80 mL), extracted with EtOAc (2×100 mL), washed with water, brine, dried over anhydrous Na2SO4, filtered, evaporated in rotavpor to give a crude. Chromatograph using EtOAc/hexane (1/9 to 7/3) gave an oily product (1.80 g, yield 76.7%). LCMS: (AA) ES+, 335, 337. 1H NMR (400 MHz, d1-chloroform) δ: 8.28-8.30 (d, J=5.27 Hz, 1H), 7.43 (s, 1H), 7.31-7.33 (dd, J=5.52, 1.51 Hz, 1H), 7.13-7.15 (d, J=8.78 Hz, 2H), 6.80-6.82 (d, J=8.78 Hz, 2H), 5.05 (s, 2H), 3.77 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.CCN(C(C)C)C(C)C.[CH3:40][N:41]1[CH2:45][CH2:44][C:43]2([CH2:49][CH2:48][NH:47][CH2:46]2)[CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:47]2[CH2:48][CH2:49][C:43]3([CH2:44][CH2:45][N:41]([CH3:40])[CH2:42]3)[CH2:46]2)[N:8]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: CN1CCC2(CCNC2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(N3CCC4(CCN(C)C4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 4 %

Procedure:
In DCM (30 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (429 mg, 0.96 mmol) and DIEA (0.22 mL, 1.12 mmol). 2-Methyl-2,7-diazaspiro[4.4]nonane (154 mg, 1.1 mmol) was then added. The reaction was conducted at ambient temperature overnight. The solvent was removed by rotary evaporation, followed by addition of water and extraction with ethyl acetate. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1) to give a white solid (20 mg, 4% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[C:25]([Mg]Br)#[C:26][CH3:27].[NH4+].[Cl-]>C1COCC1>[C:21]([O:20][C:18]([NH:3][CH2:4][CH2:5][N:6]([CH2:7][C:2](=[O:1])[C:25]#[C:26][CH3:27])[C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: CC#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A 150-mL round-bottomed flask was charged with 4-benzyl 1-tert-butyl 2-oxo-1,4-piperazinedicarboxylate (1.41 g, 4.22 mmol) and THF (5 mL). 1-Propynylmagnesium bromide (0.5 M in THF, 20.0 mL, 10.0 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at 0° C. slowly. The mixture was stirred at 0° C. for 2 h. Saturated aqueous NH4Cl (40 mL) was added and the aqueous phase was extracted with EtOAc (200 mL, then 2×100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica, 0 to 50% EtOAc in hexanes) to afford benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(2-oxo-3-pentyn-1-yl)carbamate (1.55 g) as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2].ClC1C=C2C(=CC=1)[NH:22]C=C2C1CCNCC1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([NH2:22])=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1csc2ccc([N+](=O)[O-])cc12
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1csc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-3-benzothiophencarboxylic acid 1b (20 g) was converted into the corresponding carboxylic acid chloride as in Example 2. The acid chloride was dissolved in THF (200 ml) and added dropwise to a solution of 5-chloro-3-(4-piperidinyl)-1H-indole, 9a (19 g) and triethylamine (10 ml) in THF (200 ml) at 0-5° C. The mixture was stirred overnight at room temperature. THF was evaporated. Water was added to the remaining oil. Extraction with dichloromethane (2×100 ml) and work-up of the organic extracts afforded the crude 5-nitro-3-benzothiophencarboxylic acid amide, which was subsequently purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:1). Yield 6.6 g, mp: 243-250° C. All of the amide was dissolved in 90% ethanol at reflux. Fe-powder (5 g) and concentrated aqueous HCl were added successively in small portions during 10 minutes. The mixture was refluxed for another 2.5 hours. Inorganic sags were filtered off and ethanol evaporated in vacuo. Water was added to the remaining oil and pH was adjusted to >9 by addition of diluted aqueous NH4OH Extraction with dichloromethane (2×100 ml) and subsequent work-up of the organic phase yielded 4 g of the 5-amino-3-benzothiophencarboxylic acid amide as an oil. All of this oil was dissolved in methanol (100 ml). 0.5 g of Mg turnings were added. By heating to 35° C. an exothermic reaction started. Mg turnings were added in small portions (3×0.5 g) while keeping the temperature below 45° C. The mixture was finally poured into an aqueous NH4Cl solution and concentrated aqueous HCl (1 ml) was added. Extraction with dichloromethane (2×50 ml) and work-up of the organic extracts as above afforded 2 g of the 5-amino-2,3-dihydrobenzothiophen-3-carboxylic acid amide as an oil. To a suspension of LiAlH4 (0.6 g) in dry THF (50 ml). The mixture was gently refluxed for 2 hours. After cooling to 10° C. water (2.4 ml) and a 15% aqueous NaOH solution were cautiously added to destroy excess LiAlH4. Inorganic salts were filtered off and washed extensively with THF. The combined THF solutions were evaporated leaving 1.9 g of 3-[1-(5-amino-2,3-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole as an oil.