Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]([O:27][C:28](=[O:43])[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][C:37]([NH2:39])=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:40][CH2:41][CH3:42])([CH3:26])([CH3:25])[CH3:24]>ClCCCl.O>[C:23]([O:27][C:28](=[O:43])[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][C:37]([NH:39][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:40][CH2:41][CH3:42])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCc1nc2cc(N)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (1.8 g, 8.4 mmol) was added to a solution of benzaldehyde (0.68 mL, 6.5 mmol) and (5-amino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (1.8 g, 6.5 mmol) in DCE (15 mL), and stirred overnight at room temperature. The reaction solution was diluted with H2O. The organic solution was washed with brine, dried over MgSO4, and concentrated to afford the subtitle compound that was used without further purification. MS calculated for C23H29N3O2+H: 380, observed: 380.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH2:21][NH2:22].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: COCc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Yield: 44.4 %

Procedure:
A solution of 4,6-dichloro-2-methoxymethyl-pyrimidine (250 mg, 1.3 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (196 μL, 1.3 mmol), and sodium bicarbonate (218 mg, 2.6 mmol) in EtOH (5 mL) is heated at 80° C. for three hours and poured into water (20 mL) and extracted thrice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 30% ethyl acetate:heptane to afford (6-chloro-2-methoxymethyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (200 mg, 44%) as a solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:26][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12

Procedure:
20 cm3 of sulphinyl chloride and one drop of dimethylformamide are added at a temperature in the region of 20° C. under an argon atmosphere to 1.53 g (5 mmol) of 3-carboxy-5-fluoro-1-(quinol-4-yl)-1H-indole. After stirring at reflux for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 1.8 g of 3-chlorocarbonyl-5-fluoro-1-(quinol-4-yl)-1H-indole in the form of a cream solid which is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC.O(C)[Na]>>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][C:8](=[O:9])[O:4][CH2:3]1
Reactant: CCOC(=O)OCC
Reactant: CC(C)(CO)CO
Agent: CO[Na]
Product: CC1(C)COC(=O)OC1
Temperature: 130 °C

Procedure:
A mixture of 208 grams (2 moles) 2,2-dimethyl-1,3-propanediol (neopentyl glycol), 295 grams diethyl carbonate, and 4.3 grams NaOCH3 was placed in a flask equipped with an 18-inch vigreux column and heated gradually to 130° C. About 230 ml ethanol was distilled. When the pot temperature reached 150°-160° C. excess diethyl carbonate was removed under reduced pressure. The resulting product was dissolved in benzene, washed with water, and concentrated. This product was recrystallized from ether and isolated as pure 5,5-dimethyl-1,3-dioxan-2-one. A 75 gram sample had a melting point of 108° C., very nearly matching that in the literature (109° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:41][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (130 mg, 0.276 mmol) and benzylamine (118.2 mg, 1.104 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude {4-[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]+ 515.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22](Cl)(=[O:24])=[O:23])([O-:12])=[O:11]>N1C=CC=CC=1>[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22]([O:9][C:3]1[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:24])=[O:23])([O-:12])=[O:11]
Reactant: O=c1cccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: O=c1cccccc1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 6 %

Procedure:
2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (0.54 g, 2.0 mmol) in 10 mL of pyridine to afford PZBG-4d in 6% Yield (0.04 g, 0.1 mmol). 1H NMR (400 MHz, DMSO) δ=9.00 (d, J=2.4 Hz 1H), 8.66 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 8.38 (d, J=8.8 Hz 1H), 7.66 (d, J=9.6 Hz 1H), 7.50 (td, J1=8.4 Hz, J2=3.6 Hz, J3=1.2 Hz, 1H), 7.35 (td, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.20-7.15 (m, 2H). 13C (125 MHz, DMSO) δ=178.71, 155.30, 151.20, 147.90, 140.96, 138.83, 137.10, 134.58, 133.22, 131.93, 131.55, 127.92, 121.11. ESI-MS(+): m/z 353.15 [M+H]+, 375.11 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]([CH2:7][CH2:8][S:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]([OH:6])=[O:5].O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C(Cl)CCl>CC(N(C)C)=O>[CH3:17][N:2]([CH3:1])[CH:3]([CH2:7][CH2:8][S:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]([O:6][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CN(C)C(CCSSc1ccccn1)C(=O)O
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: CN(C)C(CCSSc1ccccn1)C(=O)ON1C(=O)CCC1=O
Yield: 34.4 %

Procedure:
2-(dimethylamino)-4-(pyridin-2-yldisulfanyl)butanoic acid (218) (92 mg, 0.338 mmol), 1-hydroxypyrrolidine-2,5-dione (65 mg, 0.565 mmol) and EDC (185 mg, 0.965 mmol) was stirred in 3 ml of DMA at 50° C. overnight. The mixture was evaporated and purified on a SiO2 column eluted with from 1:10 to 1:4 of methanol/CH2Cl2 to afford 43 mg (35%) of the title product. 1H NMR (CDl3OD) 8.40 (m, 1H), 7.83 (m, 2H), 7.22 (m, 1H), 3.34 (m, 1H), 2.82 (m, 2H), 2.75 (s, 4H), 2.66 (s, 6H), 1.98 (m, 2H); 13C NMR 177.21, 161.78, 161.12, 150.68, 139.37, 122.70, 121.66, 70.80, 44.16, 43.15, 36.06, 27.38; ESI MS m/z+369.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[CH2:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.C12BC(CCC1)CCC2.[O:27]1CCCC1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([CH2:15][OH:27])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: C=C1c2ccccc2C=Cc2cc(Cl)ccc21
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCC1c2ccccc2C=Cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-chloro-5-methylene-dibenzo[a,d]cycloheptene (8.3 g) in dry tetrahydrofuran (30 ml). under an inert atmosphere, was added 9-borabicyclo [3.3.1]nonane (71 ml of a 0.5 molar solution in tetrahydrofuran) at ambient temperature and the reaction mixture was then refluxed for 3 h. After cooling. the reaction was quenched by the slow addition of 2N sodium hydroxide solution (180 ml) and 30% hydrogen peroxide (36 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a 2 h period then extracted into diethyl ether (3×250 ml). The combined organic layers were washed with brine (1×150 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on flash silica with 40% ethyl acetate in hexane as eluent to give the title compound (8.1 g) as a colourless oil. δ (360 MHz, CDCl3) 3.80 (2H. d, J=7.9 Hz CH--CH2OH), 4.18 (1H, t, J= 7.9 Hz, CH--CH2OH), 6.76 (1H, d, J=11.9 Hz, CHA =CHB) 6.89 (1H, d, J=11.9 Hz, CHA =CHB), 7.24-7.38 (7H, m, ArH); m/e 258 and 256 (M+)
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:1][C:6]2[CH:5]=[CH:4][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:7]=2)=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
This compound was prepared in an identical manner as described in Example 1, except p-nitrophenol was substituted for phenol, m.p. 142°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:48][C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=3)=[O:19])=[CH:16][N:17]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.8 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 2-amino-5-chloropyridine (29 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane and washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (27 mg, 0.051 mmol, 27%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc2[nH]cc(C(=O)c3ccc(C)c(C)c3)c(=O)c2n1
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3nc(C)ccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 65 mg (0.222 mmol) of 3-(3,4-Dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 11 mg (0.267 mmol, 60% dispersion in oil) of sodium hydride, 49.6 mg (0.267 mmol) of 2-methyl-6-bromomethyl-pyridine and 2.0 mL of N,N-dimethylformamide. The crude brown solid was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 3-(3,4-Dimethyl-benzoyl)-6-methyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C25H23N3O2 [M+H]: 398.18 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.0 min.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([NH2:17])=[NH:16])=[N:7]1.Cl.C[O-].[Na+].C(O[CH:29]=[C:30]([C:36](=O)[C:37]([F:40])([F:39])[F:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])C>CO>[CH2:34]([O:33][C:31]([C:30]1[C:36]([C:37]([F:38])([F:39])[F:40])=[N:16][C:15]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[F:2])[N:7]=2)=[N:17][CH:29]=1)=[O:32])[CH3:35]
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1C(F)(F)F
Reaction time: 12 h

Procedure:
600 mg of the crude 1-(2-fluorobenzyl)1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride (preparable from the amidine 25A by reaction with HCl) are stirred in 30 ml of methanol with 106 mg of sodium methoxide and admixed with 472 mg (1.96 mmol) of ethyl 3-ethoxy-2-trifluoroacetyl-acrylate. The mixture is boiled for 12 hours and the precipitate is then filtered off with suction and washed with ether. This gives 249 mg (27.5% of theory) of crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1.[CH2:18](O)[CH2:19][CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[C:14]2([CH2:15][CH2:16][NH:12][CH2:13]2)[O:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C1CCNC1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)NCc1ccccc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: C1COC2(CCNC2)OC1

Procedure:
Into a round bottom flask were placed 2.00 g (9.1 mmol) of 3-pyrrolidinone benzyl carbamate, from Example 1 Step 2, dissolved in 40 mL of toluene, 1.65 mL (22.8 mmol) of 1,3-propanediol and 0.09 g (0.46 mmol) of p-toluenesulfonic acid. The mixture was heated at 110°-125° C. for 48 hours. The solution was poured into 100 mL of 5% sodium bicarbonate solution, and the product was extracted into ethyl acetate, which was then dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue distilled in a kugelrohr apparatus (200° C. @ 2.5 Torr) to afford the title compound, MS: M/Z 295 (M+NH4), which was taken directly to the next step.
Reaction SMILES: [CH2:1]([CH:8]1[C:31](=[O:32])[N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21][CH:20]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:19](=[O:53])[N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:68][N:69]1[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][C:70]1=[O:76].C(=O)(O)[O-].[Na+]>FC(F)(F)S(O)(=O)=O>[CH2:46]([CH:20]1[C:19](=[O:53])[N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:68][N:69]3[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][C:70]3=[O:76])=[CH:6][CH:7]=2)[C:31](=[O:32])[N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)CC1C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Reactant: O=C1CCCCCN1CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: CC(C)CC1C(=O)OC(Cc2ccc(CN3CCCCCC3=O)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
At 0° C., 200 ml of trifluoromethanesulfonic acid were initially charged and 20 g (0.0217 mol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (1-b) (for example from Ex. 1) and 6.2 g (0.0434 mmol) of N-hydroxymethyl-ε-caprolactam were added successively, and the mixture was stirred at room temperature for 20 h. The mixture was then poured onto ice, neutralized by addition of solid sodium bicarbonate and subsequently extracted with dichloromethane. The combined extracts were washed with little water, dried and concentrated. The resulting 26 g of crude product were separated by MPLC. The first main fraction gave 1.22 g of singly amidoalkylated compound 20-benzyl-8-[4-(2-oxoazepan-1-ylmethyl)benzyl]-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (20-a). After intermediate fractions of a total of 4.21 g, 5.59 g of doubly amidoalkylated compound 8.20-bis-[4-(2-oxoazepan-1-ylmethyl)benzyl]-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (20-b) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[OH:11].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:12]([O:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Br:1])[NH:8][N:7]=[CH:6]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: Oc1cc2cn[nH]c2cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cc2[nH]ncc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 6-bromo-5-hydroxy-1H-indazole (5 g, 23.5 mmol) in THF (50 mL) is added benzyl alcohol (3.05 g, 28.2 mmol), PPh3 (7.39 g, 28.2 mmol) and diethylazodicarboxylate (4.46 mL, 28.2 mmol). After the reaction mixture is stirred at RT overnight, EtOAc (50 mL) and saturated aqueous NH4Cl (30 mL) are added. The organic phase is separated, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to provide the product (5.0 g, 70.2% yield). MS (m/z): 303.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:27][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([S:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])=[CH:11][C:12]=3[C:13]3(OCCC[O:14]3)[C:5]2=[N:4][CH2:3]1.CS(O)(=O)=O>>[CH3:1][C:2]1([CH3:28])[CH2:27][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([S:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)(=[O:20])=[O:21])=[CH:11][C:12]=3[C:13](=[O:14])[C:5]2=[N:4][CH2:3]1
Reactant: CC1(C)CN=C2N(C1)c1ccc(S(=O)(=O)N3CCCC3)cc1C21OCCCO1
Agent: CS(=O)(=O)O
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCCC4)ccc3N2C1
Temperature: 60 °C
Yield: 78.3 %

Procedure:
To 3′,3′-dimethyl-8′-(pyrrolidin-1-ylsulfonyl)-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole] (0.231 g, 0.570 mmol) was added methane sulfonic acid (6 mL) and the mixture was heated at 60° C. for 3 hr. The reaction was cooled to room temperature, poured onto ice, and basified with concentrated NH4O H to pH 11 keeping the reaction temperature below 5° C. The resulting orange solid was filtered, dissolved in CH2Cl2 and EtOAc, dried over Na2SO4, filtered, and concentrated to give the title compound as a bright yellow solid (0.155 g, 78% yield). Anal: Calc'd for C17H21N3O3S: C, 58.77; H, 6.09; N, 12.09. Found: C, 58.90; H, 6.20; N, 11.75. NMR (300 Mz, DMSO-d6): consistent. MS: (ES−) 346 [M−H]. MS: (ES+) 348 [M+H]. m.p.: 200-201° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:3]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Cl)c2N2CCOCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(CN2CCNCC2)c1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[[3-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate (800 mg, 2.02 mmol, 1.00 equiv), dichloromethane (15 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (2.5 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 580 mg (crude) of 4-[2-chloro-6-(piperazin-1-ylmethyl)phenyl]morpholine as colorless oil. LCMS (ESI, m/z): 296 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH3:42])(=[O:41])=[O:40])[C:23]=1[CH3:43].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:43])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39]([CH3:42])(=[O:40])=[O:41])=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure L using 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (76 mg, 0.28 mmol) (described herein), 4-chloro-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (97 mg, 0.28 mmol) (described herein), 4.0 M hydrochloric acid in 1,4-dioxane (0.07 mL, 0.28 mmol), and NMP (0.476 mL). After purification 1-(7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] was obtained as an orange solid. Compound is rotameric. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16-8.30 (1H, m), 7.90 and 8.00 (1H, m), 7.75-7.85 (1H, m), 7.63-7.75 (2H, m), 7.42-7.53 (1H, m), 7.28-7.39 (1H, m), 7.06-7.18 (1H, m), 6.25-6.40 (1H, m), 5.65 and 5.81 (1H, m), 4.21 (1H, m), 3.85-4.09 (3H, m), 3.69-3.83 (5H, m), 3.63 (1H, m), 3.46-3.59 (1H, m), 3.16 (1H, s), 2.91-3.13 (6H, m), 2.09-2.24 (2H, m), 1.95 (2H, m), 1.89 (1H, m), 1.66-1.79 (1H, m). Mass Spectrum (ESI) m/e=588 (M+1).