Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[O:20]=[C:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1>C1COCC1>[CH2:18]([O:17][C:13]([C:14]#[C:15][C:21]1([OH:20])[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:24]1)=[O:16])[CH3:19]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C#CC1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
n-butyl lithium (1.17 mmol, 0.47 ml, 2.5 M) was added dropwise to a solution of diisopropylamine (130 mg, 1.29 mmol, 0.18 ml) in THF (8 ml) at −78° C. The solution was warmed to 0° C., stirred for 15 mins, and cooled back to −78° C. Ethyl propiolate (126 mg, 1.29 mmol, 0.13 ml) was added dropwise and the solution stirred for 1 hr at −78° C. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (200 mg, 1.17° mmol) in THF (2 ml) was added dropwise, stirring continued for 30 mins, and the solution warmed to 0° C. and stirred for a further 15 mins. The reaction was quenched with Sat NH4Cl (20 ml) and extracted into ethyl acetate (20 ml), dried (Na2SO4), and concentrated to give a brown oil. The oil was purified by flash column chromatography eluting with 30% ethylacetate/hexanes to give the title compound as a colorless oil 0.20 g, 64%. 1H NMR (CDCl3, 400 MHz) 1.33 (3H, t), 1.48 (9H, s), 2.92 (1H, s), 4.04 (2H, d), 4.22-4.31 (4H, m).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[N+:13]([CH:16]=[CH:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCCO2
Temperature: 110 °C
Yield: 61 %

Procedure:
To 1,4-benzodioxane-6-carboxaldehyde (10.0 g, 60 mmol) in acetic acid (50 mL) was added nitromethane (6.3 mL, 1.9 eq.) and ammonium acetate (5.1 g, 1.1 eq.). After heating at 110° C. for 4 hours the mixture was cooled to ambient temperature, water (150 mL) was added, and the solid precipitate was collected by filtration. The solid was crystallized from methylene chloride-hexane (1:1, 45 mL) to obtain 7.6 g (61%) of 6-(2-nitroethenyl)-1,4-benzodioxane. To a portion of the solid (3.58 g) dissolved in MeOH-EtOH-AcOEt (1:1:1, 450 mL) was added 10% Pd/C (1.7 g) and concentrated HCl (3.3 mL, 2.3 eq). After shaking on a Parr hydrogenator at 45 psi for 5 hours, the catalyst was removed by filtration through Celite and washed with methanol. Evaporation of the filtrate gave 3.59 g (96%) of 1,4-benzodioxan-6-ethanamine, hydrochloride.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:19])[C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH:27]([CH3:29])[CH3:28])[N:22]3[C:12]2=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:19][C:14]1[C:13]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH:27]([CH3:28])[CH3:29])[N:22]3[C:12]=2[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]=1
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4ccc(OCc5ccccc5)cc4c3n21
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reaction time: 20 h
Yield: 59.2 %

Procedure:
(11S)-2-(Benzyloxy)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (530 mg, 1.36 mmol) was dissolved in ethanol (50 mL) and the solution was placed in a pressure bottle. Palladium on carbon (10%, 220 mg) was added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) for 20 hours. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/ethanol (200 mL) and the combined filtrates were concentrated under reduced pressure to give a white solid. Chromatography (SiO2, 30-50% CMA/CHCl3) gave (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (240 mg) as a white powder, mp 208-210° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=O)[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH:66]1[C:70]([CH2:71][CH2:72][CH2:73][NH2:74])=[N:69][N:68]=[N:67]1.Cl>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:74][CH2:73][CH2:72][CH2:71][C:70]4[N:66]=[N:67][NH:68][N:69]=4)=[O:29])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11]
Reactant: NCCCc1nnn[nH]1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCc5nn[nH]n5)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (Compound F1) (100 mg, 0.23 mmol) in 10 ml of anhydrous acetonitrile were added HATU (95 mg, 0.25 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol). The mixture was stirred at room temperature for 20 minutes, followed by addition of 3-(1H-tetrazol-5-yl)propan-1-amine hydrochloride (57 mg, 0.35 mmol). The mixture was stirred at room temperature for another 40 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 8˜12% methanol in chloroform containing 0.5% of triethylamine to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 50 mg, 40%.
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]
Reactant: COc1ccccc1C1(O)c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1C1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Yield: 82 %

Procedure:
Using N-(3-hydroxy-3-(2-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 246, the title compound was synthesized in the same manner as in Example 271. Yield: 82%. Melting point: 169-170° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.ClC1C=C(C=CC=1)C(O)=O.C([O-])(=O)C.[Na+]>ClCCl.C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[CH:10][C:11]3([CH:14]=2)[CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CC3)C2)cc1
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(C2=CC3(C=C2c2ccc(F)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.3 %

Procedure:
A solution of 300 mg (0.88 mmol) of 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide (from Step 1) in 5 mL of dichloromethane was treated with 300 mg (55% peroxyacid, 0.96 mmol) of m-chloroperoxybenzoic acid (MCPBA). The reaction was stirred at ambient temperature for 2.5 hours, washed with aqueous saturated sodium bisulfite, dried (MgSO4), and concentrated in vacuo to give a mixture of desired expoxide intermediate and m-chlorobenzoic acid; this crude mixture in 6 mL of acetic acid and 0.6 mL of water was subsequently treated with 300 mg (3.7 mmol) of sodium acetate and stirred at 80° C. for 10 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate; the organic phase was washed with aqueous saturated sodium bicarbonate, water, brine, dried (MgSO4), and reconcentrated in vacuo. Purification by silica gel chromatography gave 118 mg (39%) of 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide as a colorless solid: mp 110°-116° C. (dec); NMR (CDCl3) δ1.80 (s, 4H), 4.81 (br s, 2H), 6.21 (d, J=2 Hz, 1H), 6.33 (d, J=2 Hz, 1H), 6.94 (t, J=9 HZ, 2H), 7.06-7.15 (m, 2H), 7.29 d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H),
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:17].CCN(C(C)C)C(C)C.Cl[C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:37]3[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=3)[CH2:13][CH2:12]2)[C:6]1=[O:17]
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](Oc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Yield: 38.3 %

Procedure:
A stirred solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (Preparation G; 18 mg, 0.047 mmol), DIEA (24 μL mL, 0.14 mmol), and 2-chloro-5-ethylpyrimidine (20 mg, 0.14 mmol) in DMF (1 mL) was heated at 100° C. for 2 hours in a sealed tube. The mixture was cooled, diluted with EtOAc (25 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/DCM 4:1) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1′-(5-ethylpyrimidin-2-yl)-[1,4′-bipiperidin]-2-one (9 mg, 0.018 mmol, 38% yield) as a white solid. Mass spectrum (apci) m/z=495.1.
Reaction SMILES: [Li+].[BH4-].CO.C[O:6][C:7]([C:9]1([CH2:13][CH2:14][CH3:15])[CH2:12][CH2:11][CH2:10]1)=O.[OH-].[Na+]>CCOCC>[CH2:13]([C:9]1([CH2:7][OH:6])[CH2:12][CH2:11][CH2:10]1)[CH2:14][CH3:15]
Reactant: CCCC1(C(=O)OC)CCC1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCC1(CO)CCC1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
LiBH4 (524 mg, 24 mmol) and methanol (1 mL) were added to a 0° C. solution of 1-2 (1.935 g, 11.4 mmol) in ether (22 mL). After 1 h at 0° C. and 1.5 h at room temperature, 41 mL 2 M NaOH was slowly added and the resulting mixture was stirred for 1 h. The mixture was then extracted with dichloromethane (3×40 mL) and the combined dichloromethane solution was washed with saturated NH4Cl solution and brine (150 mL each). The organic solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (dichloromethane) gave 1-3 (1.229 g, 87%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][CH2:12][OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:13][CH2:12][CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: OCCBr
Reactant: c1ccc2c(c1)CNC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCN1Cc2ccccc2C1
Yield: 62.7 %

Procedure:
A solution of 2.85 g (0.0252 mol) of isoindoline, 2.99 g (0.0252 mol) of 2-bromoethanol and 5.09 g (0.05 mol) of triethylamine in 100 ml of dry toluene was refluxed for 12 hours. After cooling the mixture was filtered, concentrated in vacuo, dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield 2.58 g (63%) of a dark red oil. NMR: (CDCl3) δ 2.78 (2H, t), 3.52 (2H, t), 3.82 (4H, s), 7.0 (4H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:27][N:24]1[CH2:23][CH2:22][N:21]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:20])=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N5CCCC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and pyrrolidine (Aldrich Cat. No. P73803). LCMS (M+H)+: m/z=422.2.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:21])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22]NC.O1CCOCC1>>[CH3:22][N:8]=[C:7]([C:11]1[C:12](=[O:21])[C:13]2[C:18]([C:19](=[O:20])[C:10]=1[OH:9])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)c2c(-c3ccccc3)noc21
Reactant: CNC
Solvent: C1COCCO1
Product: CN=C(C1=C(O)C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
A solution of 3-phenyl-4,9-dihydronaphtho[2,3-d]-isoxazole-4,9-dione (1.0 g) in 6.6 % dimethylamine-dioxane solution (100 ml) is irradiated by light of a high-pressure mercury lamp (1 KW) through a pyrex filter at room temperature (20°-30°C) in argon atmosphere for 3.3 hours. After removal of the solvent, the residue is dissolved in methylene chloride. The solution is washed with water, dried with anhydrous sodium sulfate, and evaporated. The residue is washed with benzene to give 2-(N-methylbenzimidoyl)-3-hydroxy-1,4-naphthoquinone (252 mg). Recrystallization from methanol gives yellow prisms, m.p. 235°-237°C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.CCOCC.C(OCC)(=O)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccnc4)ccc32)n1)c1ccccc1
Temperature: 100 °C

Procedure:
A stirred solution of 2-[(S)-1-phenylethylamino]-4-[5-(tributylstannyl)-benzimidazol-1-yl]pyrimidine (27 mg), 3-bromopyridine (44 μL) and tetrakis(triphenylphosphine)palladium(0) (0.5 mg) in DMF (4 mL) was heated and maintained at 100° C. overnight. The reaction mixture was cooled and transferred to a separatory funnel containing 100 mL ether plus 25 mL ethyl acetate. The organic layer was washed 3× with water and 1× with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography eluting with methanol in dichloromethane to give 9.1 mg of the title compound. Mass spectrum (ESI): 393.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([OH:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[C:42]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([O:36][CH3:42])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1OC
Reaction time: 16 h

Procedure:
To a mixture of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoate (100 mg, 0.18 mmol) in 2 mL of DMF were added MeI (38 mg, 0.27 mmol) and K2CO3 (37 mg, 0.27 mmol) at room temperature, and then the mixture was stirred for 16 hours. The mixture was poured into water and extracted with EtOAc (3×5 mL). The organic layer was washed with 0.1 N HCl (5 mL) and brine. The organic layer was dried over Na2SO4. After filtration and concentration, the crude methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-methoxybenzoate was obtained and used the next step without purification (80 mg, 78%). LC-MS: 565 [M+H]+, tR=1.48 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1.[CH3:15]C(CC1C=CC(CO)=CC=1)C(O)=O>>[CH3:15][CH:10]([CH2:9][C:6]1[CH:7]=[N:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)/C=C/c1ccc(CO)nc1
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Product: CC(Cc1ccc(CO)nc1)C(=O)O

Procedure:
The title compound was prepared from Intermediate G acid by the same methodology used to make Intermediate B.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)(O)[O-].[Na+]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C

Procedure:
A suspension of 4-(1H-indazol-3-yl)piperazine (1.6 g, 7.9 mmol), N-(2-bromoethyl)phthalimide (2.1 g, 7.9 mmol), and sodium bicarbonate (0.7 g, 8.3 mmol) in acetronitrile (160 ml) was warmed to reflux for 24 hours. Upon cooling to room temperature, the reaction mixture was filtered through a pad of celite and the solids were washed with DCM. The combined filtrates were concentrated to give the N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][NH:10][C:11]([CH:13]1[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1)=O.FC(F)(F)C([O-])=O.[NH4+:34]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:34]=[C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)[NH:10][CH:9]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccccc1Cl
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: Clc1ccccc1-c1c[nH]c(C2CN(Cc3ccccc3)CCO2)n1
Temperature: 150 °C
Yield: 96.3 %

Procedure:
A mixture of N-[2-(2-chlorophenyl)-2-oxoethyl]-4-(phenylmethyl)-2-morpholinecarboxamide (350 mg, 0.939 mmol) and ammonium trifluoroacetate (615 mg, 4.69 mmol) was heated at 150° C. for 1.5 hours. Water (150 mL) was added to the residue, and the mixture was extracted with EtOAc (3×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated to afford the title compound (320 mg) as a brown solid. LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:43])[CH2:22][O:23]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:44](Cl)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1COCC1>[CH2:44]([O:43][CH:21]([CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:22][OH:23])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: ClCc1ccccc1
Reactant: OC(COCCCCCCCCCCCCC1CCCCC1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(COCCCCCCCCCCCCC1CCCCC1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 452.2 %

Procedure:
A mixture of 35 g (4.6 mmole) of 1-(12-cyclohexyldodecyloxy)-3-trityloxy-2-propanol prepared in Reference Example 11, 8.7 g (69 mmole) of benzyl chloride, 0.5 g of cetyltrimethylammonium chloride, 7.4 g (92 mmole) of 50% aqueous sodium hydroxide solution and 50 ml of THF was stirred at 60° C. overnight. To the reaction mixture were further added 7.4 g (92 mmole) of 50% aqueous sodium hydroxide solution and 8.7 g (69 mmole) of benzyl chloride, and the resulting mixture was stirred overnight. THF was distilled off from the mixture, and 100 ml of hexane was added to the residue. The mixture was washed with water and then hexane was distilled off. To the residue were added 120 ml of dioxane and 60 ml of 1N hydrochloric acid, and the mixture was stirred at 80° C. for 5 hours. After the mixture was cooled and neutralized with sodium bicarbonate, 100 ml of ethyl acetate was added to the mixture. The organic layer was washed with water and dried (MgSO4), and then the solvent was distilled off. The residue was allowed to stand at room temperature overnight. A small amount of hexane was added to the residue and the deposited tritylalcohol was filtered off. The filtrate was subjected to column chromatography on silica gel (500 g) and eluted with hexane-ethyl acetate (9:1) to give 9.0 g (yield: 45%) of the above-mentioned compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[O:30])=[CH:32][CH:33]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(NC(=O)Cc2ccc(C(=O)O)cc2)c2ccccc2N2CCCCC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(NC(=O)Cc2ccc(C=O)cc2)c2ccccc2N2CCCCC2)cc1
Temperature: 170 °C

Procedure:
Quantities of 8.85 gm (20 m mol) of 4-{N-[α-(4-Methylphenyl)-2-piperidino-benzyl]-aminocarbonylmethyl}-benzoic acid and 3.25 gm (20 m mol) of N,N'-carbonyldiimidazole were refluxed in 100 ml of absolute tetrahydrofuran for two hours. Then, the mixture was concentrated by evaporation, and, after addition of 50 ml of pyridine and 3.7 gm (20 m mol) of 4-toluene-sulphonic acid hydrazide, the mixture was refluxed for a further two hours. The mixture was then poured onto ice water and subjected to suction filtration, and the precipitate was dried. The resulting crude toluene-sulphonic acid hydrazide of the carboxylic acid used was mixed with 20 gm of anhydrous sodium carbonate and heated to 170° C. in 50 ml of ethylene glycol for two hours. Then, it was added to water and extracted with chloroform. The concentrated extracts were purified by column chromatography on silica gel by use of toluene/ethyl acetate (5:1) as eluant.