Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 9, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@@H:4]([NH2:18])[CH2:3][C@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C[C@H](F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 153 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.61-7.41 (m, 4H), 7.27 (dd, J=14.5, 5.8 Hz, 2H), 4.84-4.56 (m, 1H), 3.67 (d, J=7.4 Hz, 3H), 3.44-3.34 (m, 2H), 3.21-2.86 (m, 3H), 2.22-2.07 (m, 1H), 1.87 (ddt, J=34.3, 21.1, 7.4 Hz, 3H), 1.70-1.53 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O.[CH2:34]1COCC1.O>>[CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:34])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Product: Cc1cnc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1

Procedure:
A solution of 33.9 mg (0.08 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoate (Compound 15a) and 8.5 mg (0.20 mmol) of LiOH-H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. PMR (d6-DMSO): δ 1.29 (6H, s), 2.42 (2H, d, J=4.6 Hz), 6.68 (1H, t, J=4.6 Hz), 7.51 (2H, m), 7.62 (2H, d, J=8.2 Hz), 7.77 (1H, d, J=3.3 Hz), 7.93 (2H, d, J=8.2 Hz), 7.98 (1H, d, J=3.3 Hz).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][C:26]=1[F:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[F:33])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cc(CCl)ccc1OCc1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 400 mg, 10.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (1.852 g, 10.0 mmol) in DMF (50 mL) at room temperature. The mixture was stirred for 1 h at this temperature and 1-benzyloxy-4-chloromethyl-2-fluoro-benzene (CAB03018, 2.51 g, 10.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (200 mL) and water (50 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (40 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 3.12 g (78%). 1H-NMR (400 MHz, d6-DMSO) δ=4.97 (s, 2H), 5.12 (s, 2H), 6.73 (d, J=9.0 Hz, 2H), 7.01 (dd, J=8.2, 1.2 Hz, 1H), 7.16 (dd, J=8.6, 8.6 Hz 1H), 7.21 (dd, J=8.6, 2.4 Hz, 1H), 7.30-7.44 (m, 5H), 7.75 (d, J=9.0 Hz, 2H), 8.80 (s, 2H). LRMS (FAB+): 400.1 (100, [M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O.C(N(CC)C1C=CC=CC=1)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:20])[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2nccn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: Clc1nc(-c2ccc(Br)cc2)cc2nccn12
Temperature: 50 °C
Yield: 39 %

Procedure:
To a flask charged with 7-(4-bromophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (25.00 g, 86.173 mmol), phosphoryl trichloride (31.554 mL, 344.69 mmol), and N,N-diethylaniline (27.420 mL, 172.35 mmol) was added acetonitrile (200 mL) and the mixture was heated to 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue diluted with water and DCM. The aqueous was neutralized with potassium carbonate and the bi-phasic mixture passed through a pad of celite to remove the insoluble material. The layers were separated and the aqueous extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was triturated with hexanes and the solids were collected by filtration to afford 7-(4-bromophenyl)-5-chloroimidazo[1,2-c]pyrimidine (10.369 g, 33.604 mmol, 38.997% yield). MS (apci) m/z=310.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:13][C:14](ON1C(=O)CCC1=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([O:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCN
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Product: NCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1,3-Diaminopropane (35.5 g, 0.48 mol) was dissolved in 300 mL CHCl3, and the solution was cooled to 0° C. A solution of N-(benzyloxycarbonyloxy)succinimide (4.5 g, 0.018 mol) in 150 mL CHCl3 was added dropwise over 6 h, with the internal temperature maintained below 10° C. After addition was complete, the reaction solution was stirred at room temperature overnight. The solution was washed with water, dried (Na2SO4), filtered and concentrated in vacuo to provide 3.0 g (80%) of the title compound as a low melting solid: 1H NMR (CDCl3) δ 1.25 (bs, 2 H), 1.63 (quintet, 2 H), 2.77 (t, 2 H), 3.2-3.34 (bm, 2 H), 5.09 (s, 2 H), 5.37 (bm, 1 H), 7.28-7.40 (m, 5 H); MS, m/e 209 ((M+H)+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]([F:21])([F:20])[F:19])[CH:10]=1.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:25][CH2:26][C:27]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]([F:19])([F:20])[F:21])[CH:10]=1)=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1ccc(N)cc1OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C#N)c(OC(F)(F)F)c1
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
Triethylamine (6.5 g, 64.2 mmol) was added to a stirred solution of 4-amino-2-[(trifluoromethyl)oxy]benzonitrile (Intermediate 51, 6.5 g, 32.2 mmol) in DCM (100 mL) at 0° C. and the mixture was stirred for 15 min. Chloro-2-oxoethyl acetate (5.2 g, 38.1 mmol) was added at 0° C. and stirring was continued for 4 hr at room temperature. The reaction mixture was diluted with DCM and washed with ice-water, saturated aq. NaHCO3 solution and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 30% EtOAc/pet ether to give the title compound (8.10 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:24][CH3:25])[CH:5]=1.O.[OH-].[Li+]>CO>[CH3:25][O:24][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][N:15]=1)=[O:12])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C(F)(F)F)cn2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)Nc1cnc(C(F)(F)F)cn1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-methoxy-4-[3-(5-trifluoromethyl-pyrazin-2-yl)-ureido]-benzoic acid methyl ester (213 mg, 0.575 mmol) in 5.75 mL 3:1 MeOH:H20 at room temperature under nitrogen was added lithium hydroxide monohydrate (240 mg, 5.8 mmol) and the reaction warmed to 65° C. After reaching temperature, the suspension gradually became a bright yellow solution. After about 4 hours a precipitate formed but the reaction was continued overnight. After cooling to RT, MeOH was removed by rotovap and the aqueous suspension neutralized to pH=5 with concentrated HCl. As pH=5 was approached, the suspension turned from yellow to white. The suspension was then filtered through paper on a ceramic funnel. When most of the H20 was removed the residue was dryed under high vacuum in a dessicator overnight (133 mg, 55%).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([Si:10]([O:13][CH:14]([C:19]1([CH2:23][CH2:24][CH3:25])[CH2:22][CH2:21][CH2:20]1)[CH2:15][CH:16]=[CH:17]I)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[CH2:26]=[O:27]>CCCCC.C1COCC1>[Si:10]([O:13][CH:14]([C:19]1([CH2:23][CH2:24][CH3:25])[CH2:22][CH2:21][CH2:20]1)[CH2:15][CH:16]=[CH:17][CH2:26][OH:27])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CCCC1(C(CC=CI)O[Si](C)(C)C(C)(C)C)CCC1
Reactant: C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCC1(C(CC=CCO)O[Si](C)(C)C(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
tert-Butyllithium (1.32 mL of a 1.7M solution in pentane, 2.25 mmol) was added to a solution of the vinyl iodide 6 (460 mg, 1.25 mmol) in THF (2.2 mL) at −78° C. After 0.5 h paraformaldehyde (50 mg, 1.67 mmol) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 4:1 hex/EtOAc) yielded 103 mg (33%) of the alcohol 7 as a clear, colorless oil.
Reaction SMILES: C(N(C(C)C)C(C)C)C.N1([C:15]2[CH2:19][CH2:18][CH2:17][CH:16]=2)CCCC1.Br[CH2:21][C:22]1[C:23]([CH2:28]Br)=[CH:24][CH:25]=[CH:26][CH:27]=1.Cl.[OH2:31]>C(#N)C>[O:31]=[C:19]1[CH:18]2[CH2:17][CH2:16][CH:15]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]2
Reactant: BrCc1ccccc1CBr
Reactant: O
Reactant: C1=C(N2CCCC2)CCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C2CCC1Cc1ccccc1C2
Yield: 72 %

Procedure:
Ethyl diisopropylamine (10.3 g, 13.9 mL, 79.8 mmol) and a solution of 1-pyrrolidino-1-cyclopentene (5.2 g, 5.5 mL, 37.8 mmol) in acetonitrile (75 mL) were added successively to a vigorously stirred solution of α,α′-dibromo-o-xylene (10.0 g, 38.0 mmol) in acetonitrile (75 mL) and the resultant mixture was heated to reflux under nitrogen for 18 hours. Water (75 mL) was added and the mixture was heated for an addition 1 hour. Then the solution was cooled and 10% hydrochloric acid (38 mL) was added. Most of the volatiles were removed in vacuo, and the resultant residue was extracted with ether (4×100 mL). The combined ethereal extracts were washed successively with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified using flash column chromatography (“FCC”) to provide 11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (5.1 g, 72%).
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:34]>C(O)C>[NH2:34][CH2:22][CH2:21][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9]
Reactant: N
Reactant: CCCCCCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Solvent: CCO
Product: CCCCCCN(CCN)S(=O)(=O)c1cccc2cnccc12
Temperature: 90 °C

Procedure:
To 2.34 g of the thus obtained N-hexyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide was added 40 ml of an ethanol solution containing 4 g of ammonia, and the mixture was heated at 90° C. for 48 hours in a pressure vessel. Then, the solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: a 3% methanol solution in chloroform) to obtain 1.34 g of N-hexyl-N-(2-aminoethyl)-5-isoquinolinesulfonamide [Compound (4)]. Compound (4) was analyzed to give the following data.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]3[N:22]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[C:18]3[CH2:17]2)=[O:15])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]3[N:22]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]([I:1])=[C:18]3[CH2:17]2)=[O:15])=[CH:33][CH:34]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
N-iodosuccinimide (70 mg, 0.31 mmol) was added to a solution of 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.1 g, 0.28 mmol) in chloroform (1 mL). The mixture was stirred at 65° C. for 1 hour. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.13 g, 96% yield) as a white solid.
Reaction SMILES: [ClH:1].[Cl:2]CCCO[C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15](OCCCCl)[CH:16]=1)[CH:11]=2.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[ClH:2].[ClH:1].[ClH:2].[CH2:26]([NH:30][CH2:13][CH2:12][CH2:11][C:15]1[CH:14]=[CH:13][C:12]2[C:17]([CH:16]=1)=[N:18][C:19]1[C:10](=[CH:9][CH:8]=[C:7]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:10][CH2:9][CH3:8])[CH:20]=1)[CH:11]=2)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Agent: Cl
Product: CCCCNCCCc1ccc2cc3ccc(CCCNCCCC)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and n-butylamine as described in Example 15, giving 2.0 g. of the desired product as orange crystals, m.p. 247°-249° C.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:30]O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:30][Br:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CBr)OCc1ccccc1

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar, 2.00 g (4.6 mmoles) of 1-O-octadecyl-2-O-benzyl-glycerol (Bachem, Switzerland) was dissolved into 120 ml of toluene. To this solution were added 4.58 g. (13.8 mmoles) of carbon tetrabromide and 3.62 g. (13.8 mmoles) of triphenylphosphine and the reaction mixture stirred for 4 hours at room temperature. The yellow suspension was filtered and the filtrate concentrated on a rotary evaporator to afford a white solid. This residue was dissolved into 50 ml chloroform, washed twice with 30 ml saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under vacuum on a rotary evaporator to afford 2.5 g of the crude product as a white powder. This crude product was purified by flash column chromatography on a silica gel 60 (E. Merck, Germany) column by sequential elution with 100 ml each of hexane, 1% ethyl acetate in hexane, 2% ethyl acetate in hexane and finally with 3% ethyl acetate in hexane. Fractions collected were screened by TLC and those fractions that contained pure product (silica gel, 5% ethyl acetate in hexane, Rf=0.56) were pooled. The pooled fractions were concentrated under vacuum on a rotary evaporator to afford a quantitative yield of the 1-O-octadecyl-2-O-benzyl-3-bromo-1,2-propanediol as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][CH:7]=[CH:6][N:5]2[CH:18]=1.[N:19](OCCCC)=[O:20]>O1CCOCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[CH:6][N:5]2[C:18]=1[N:19]=[O:20]
Reactant: CCCCON=O
Reactant: Cc1cn2ccnc(OCc3ccccc3)c2n1
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3ccccc3)nccn2c1N=O

Procedure:
A solution of 14.2 g 2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine, 129.3 g n-butyl nitrite and 142 ml p-dioxane was heated under reflux for 0.5 hr. and decanted from a small amount of gum. The supernatant solution was stirred under vacuum (40°/0.1 mm) and the residue azeotroped with cyclohexane to give 2-methyl-3-nitroso-8-phenylmethoxyimidazo[1,2-a]pyrazine as a soft, green solid which was identified by pmr and ms and immediately reduced (as in Example 6) without further purification.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:9]=1[CH:28]=[C:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH3:7].C(OCC)C.O1CCCC1>C(OCC)C.[Cu]I>[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[C:9]=1[CH:28]([CH:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH2:1][CH2:2][CH3:3])[CH3:7]
Reactant: CCC[Mg]Cl
Reactant: CCc1nc2sc3c(c2c(-c2ccc(C)cc2)c1C=C1SC(=O)NC1=O)CCCC3
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C1SC(=O)NC1=O
Reaction time: 0.33 h
Yield: 9 %

Procedure:
To a cold (−15° C.) solution of copper(I)iodide (0.200 g; 1.05 mmol) in anhydrous diethyl ether (5 mL) was added a 2M solution of n-propylmagnesium chloride in diethyl ether (1.0 mL; 2.0 mmol). The mixture was stirred for 20 min and a solution of 5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methylene]thiazolidine-2,4-dione (0.083 g; 0.197 mmol) in a mixture diethyl ether-tetrahydrofurane (2/1, 3 mL) was added dropwise and stirring was carried on for 2 h at −15° C. and 18 h at room temperature. The reaction was quenched with a saturated solution of ammonium chloride (50 mL) and diluted with diethyl ether (20 mL). Both phases were separated, the aqueous layer was extracted with diethyl ether, the combined organic phases were washed with a saturated solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.008 g (9%) of the title compound.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.[Li]C(CC)C.[C:14]([C:18]1[CH:26]=C[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CI>C1COCC1>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[C:3]([CH3:4])[CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: [Li]C(C)CC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
A 250 mL round bottom flask was charged with tetramethylethylene diamine (5.6 mL, 37 mmol) in THF (34 mL). After the mixture was cooled to −92° C. (N2(liq)/CH2Cl2 bath), sec-BuLi (26.5 mL, 37 mmol, 1.4M solution in cyclohexane) was added, followed by the dropwise addition of a solution of 4-tert-butylbenzoic acid (3 g, 16.8 mmol) dissolved in THF (22 mL). After stirring for 1 h, methyliodide (4.5 mL, 72.4 mmol) was added to mixture at −80° C. After stirring for 10 min at −80° C., the reaction mixture was quenched H2O (20 mL). Upon warming to room temperature, the aqueous phase adjusted to pH=2 with aqueous HCl (1M). The aqueous phase was extracted with EtOAc (2×15 mL), and the combined organic extracts were dried with Na2SO4 and concentrated. The residue was chromatographed with (gradient, 10%-60% EtOAc/hexanes) to afford 630 mg (20%) 101a.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17]([C:22]5[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=5)=[CH:16][C:15]=4[NH:14][C:13]=3[C:12]([C:28]#[N:29])=[CH:11][N:10]=2)[C@H:4]([CH3:30])[CH2:3]1.OO.C(=O)([O-])[O-:34].[K+].[K+]>CS(C)=O>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17]([C:22]5[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=5)=[CH:16][C:15]=4[NH:14][C:13]=3[C:12]([C:28]([NH2:29])=[O:34])=[CH:11][N:10]=2)[C@H:4]([CH3:30])[CH2:3]1
Reactant: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3cc(-c4cnn(C)c4)ccc3c12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C(N)=O)c2[nH]c3cc(-c4cnn(C)c4)ccc3c12
Temperature: 70 °C

Procedure:
To a stirred solution of 1-{[(1R,2R,4R)-4-hydroxy-2-methylcyclohexyl]amino}-7-(1-methyl-1H-pyrazol-4-yl)-5H-pyrido[4,3-b]indole-4-carbonitrile (15 mg, 0.037 mmol) in DMSO (2 mL) were added hydrogen peroxide (30%, 0.038 mL, 0.38 mmol) and potassium carbonate (28 mg, 0.20 mmol). The reaction mixture was heated to 70° C. overnight, cooled to room temperature, filtered, and purified by prep-HPLC to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.42 (s, 1H); 8.07 (d, 1H); 7.99 (s, 1H); 7.88 (s, 1H); 7.77 (s, 1H); 7.48 (dd, 1H); 3.97 (m, 1H); 3.93 (s, 3H); 3.69 (m, 1H); 1.22-2.17 (series of m, 7H); 1.03 (d, 3H). LRMS (APCI) calc'd for (C23H26N6O2) [M+H]+, 419.2. found 419.1.