Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[C:19](I)=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:23]4[CH:24]=[N:25]N(C)[CH:27]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[C:29]([Cu])#[N:30].[CH3:32][N:33](C=O)C>CCOC(C)=O.[NH4+].[OH-]>[C:6]([CH2:5][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[C:19]([C:32]#[N:33])=[CH:20][N:21]=[C:17]3[CH:16]=[C:15]([C:23]3[CH:24]=[N:25][N:30]([CH3:29])[CH:27]=3)[N:14]=2)[CH:10]=[N:9]1)[CH:1]1[CH2:3][CH2:2]1)#[N:7]
Reactant: Cn1cc(-c2cc3ncc(I)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3ncc(C#N)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 160 °C
Yield: 62 %

Procedure:
In a microwave safe flask, 3-cyclopropyl-3-(4-(3-iodo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (22.4 mg, 0.0463 mmol) and cyanocopper (4.56 mg, 0.0509 mmol) were suspended in DMF (463 μL, 0.0463 mmol). The reaction mixture was heated at 160° C. for 1 hour. The reaction mixture was cooled and diluted in EtOAc and 10% NH4OH (10 mL). The mixture was separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Purification using preparative TLC in 15% MeOH/EtOAc afforded 5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-3-carbonitrile (11.0 mg, 62.0% yield). MS (apci) m/z=384.4 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Br:15])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)c1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To tert-butyl(2-bromo-3-chlorophenyl)carbamate (0.4 g) in DCM (20 mL) was added TFA (10 mL). The reaction mixture was stirred at RT for 3 hours and then concentrated. Water (10 mL) was added to the residue, and the mixture was extracted with DCM (2×20 mL). The organic phase was separated, washed with aqueous saturated NaHCO3 and saturated NaCl, dried over anhydrous Na2SO4, and concentrated to give the title compound as a solid (0.2 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.03-6.99 (1H, m), 6.85-6.83 (1H, d, J=8.0 Hz), 6.65-6.63 (1H, d, J=8.0 Hz), 4.25 (2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18](O)[CH:19]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=2)O1>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([C:29]2[CH:30]=[CH:31][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:42][CH:43]=2)[CH:17]=[C:11]([C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN(C)C(=O)c1cc(O)cc(OCc2ccccc2)c1
Product: CN(C)C(=O)c1cc(OCc2ccccc2)cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 58 using 3-benzyloxy-5-hydroxy-N,N-dimethylbenzamide instead of 4-hydroxy-3-methoxybenzaldehyde and tert-butyl N-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane-2-yl)bezyl]carbamate instead of phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([OH:26])=O)=[N:13]2)=[O:10])=[CH:4][CH:3]=1.[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH2:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:13]=[C:14]([CH2:23][C:24]([NH:30][CH2:29][C:28]([CH3:32])([CH3:31])[CH3:27])=[O:26])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CN
Reactant: O=C(O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: CC(C)(C)CNC(=O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 114 and 2,2-dimethylpropan-1-amine were treated using a method similar to that described in Example 112 to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.48-8.41 (m, 1H), 8.30 (bs, 1H), 7.97 (d, J=8.0, 1H), 7.92-7.76 (m, 2H), 7.38 (bs, 4H), 6.11-5.98 (m, 1H), 3.89 (s, 2H), 3.80 (bs, 2H), 3.02 (d, J=6.3, 2H), 0.80 (s, 9H); MS (ESI−) M/Z 439 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([Mg]Br)[CH2:36][CH3:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:35][CH2:36][CH3:37])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC[Mg]Br
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(CCCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 64A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Preparation 63A) and propylmagnesium bromide, the title compound was obtained as a foam-like substance.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.O.S([O-])(O)=O.[Na+]>ClCCl>[C:1]1([CH:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH:9]2[O:25][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(C(CC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.52 g of 4,4-diphenylbut-1-ene in 25 mL of dichloromethane at 0° C. was added 0.75 g of 50-60% by wt of m-chloroperbenzoic acid. The mixture was stirred at room temperature overnight, then heated at reflux for 1 hr. Water, 1 mL, and 0.25 g of sodium hydrogen sulfite were added to destroy the excess oxidizing agent. The organic layer was washed with water and dilute sodium hydrogen carbonate solution, dried, then concentrated in vacuo to give 0.5 g of 4,4-diphenylbut-1-ene oxide which is characterized by:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:16]1[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]=1[CH3:25].O>CN(C)C=O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][S:12][C:16]2[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]=2[CH3:25])=[CH:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CS)cc1
Reactant: CCn1ncc(Cl)c(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc(SCc2ccc(C(C)(C)C)cc2)c(C)c1=O
Yield: 56.2 %

Procedure:
To 3 ml of dry N,N-dimethylformamide was added 0.024 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and was added dropwise with a solution of 1 g of p-t-butylbenzyl mercaptan dissolved in 5 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 0.67 g of 5-chloro-2-ethyl-4-methyl-3(2H)-pyridazinone dissolved in 5 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was allowed to stand over night. The resulting solution was poured into 30 ml of water and extracted twice with 30 ml of diethyl ether. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate, and freed of solvent by distillation under reduced pressure to give 1.42 g of a crude product. The crude product was separated and purified by thin layer chromatography (silica gel, benzene) to obtain 0.69 g of 5-(p-t-butylbenzylthio)-2-ethyl-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=1[C:20]([NH:22][CH2:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2)=[O:21].C(OC([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=O)(C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCCC1=O.C(OCC)(=O)C>[ClH:10].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:17])=[CH:13][C:12]=1[C:20]([NH:22][CH2:23][C:24]12[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C(=O)N2CCNCC2)ccc1Cl
Yield: 102.5 %

Procedure:
Ethyldiisopropylamine (0.3 ml) was added at ambient temperature to a solution of 4-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-isophthalamic acid (0.15 g, Example 60a), piperazine-1-carboxylic acid tert-butyl ester (0.16 g) and PyBrOP (0.40 g) in N-methylpyrrolidinone (10 ml). After 5 h the reaction mixture was diluted with ethyl acetate and washed twice with water, twice with 10% KHSO4 solution, twice with saturated NaHCO3 solution and once with brine, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with ethanol (0-5%) in dichloromethane), then redissolved in methanol (10 ml) and treated with hydrochloric acid (4N dioxane, 1 ml). After 48 h the reaction mixture was concentrated under reduced pressure and recrystallised from iso-hexaxne/propan-2-ol to yield the title compound as a solid (0.10 g).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.N1C=CC=CC=1.[CH3:29][CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>C(O)C>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([CH3:29])[CH2:35]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CC1CNCCN1
Solvent: CCO
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 1 but starting from 2.1 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 20 cm3 of pyridine and 2.4 g of 2-methylpiperazine. After taking up in ethanol and concentrating to dryness under reduced pressure (20 kPa at 50° C.), the solid residue is taken up in 20 cm3 of water and 10 cm3 of 2 N potassium hydroxide solution. The aqueous solution obtained is washed with twice 20 cm3 of trichloromethane, 10 cm3 of acetic acid are added and the mixture is again washed with twice 40 cm3 of trichloromethane. 23 cm3 of 4.5 N potassium hydroxide solution are added and the suspension obtained is heated to a temperature close to 90° C. After cooling to a temperature close to 20° C., the precipitate is drained and washed with 3 times 10 cm3 of water and twice 10 cm3 of ethanol. After recrystallizing twice from 120 cm3 of dimethylformamide each time, 1.7 g of 1-ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 310°-312° C.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]3[OH:31])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:33][C:34]1[CH:35]=[CH:36][C:37]2[O:42][CH2:41][C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=2[CH:49]=1>>[CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH:19]3[O:31][CH2:33][C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=4[CH:49]=3)=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC3CCCCC3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOC4CCCCC4)cc3)cc21

Procedure:
Analogously to Method D, 0.470 g of tert-butyl 4-[4-(3-cyclohexyloxypropoxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 0.324 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.46 (1:1 EtOAc-heptane); Rt=6.20.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][CH2:17][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[C:25]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:24]2=[N:23][C:22]=3[NH2:33])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.O>[NH2:33][C:22]1[C:21]2[N:20]=[CH:19][C:18]([CH2:17][CH2:16][C:15]3[CH:34]=[CH:35][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=3)=[CH:27][C:26]=2[C:25]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:24]=2[N:23]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCO)cc3)cc12
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 equiv.) in tetrahydrofuran (0.10 M) was added a 1.0 M solution of tetrabutylammonium fluoride (5 equiv.) in THF and the resulting mixture was allowed to stir at 22° C. for 2 hours. At this point, the mixture was diluted with ethyl acetate and water. The biphasic layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-10% methanol in dichloromethane to furnish 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)ethanol as a solid. 1H NMR (Acetone-d6): δ 8.76 (s, 1H), 8.67 (s, 1H), 8.28 (d, 1H), 7.40 (s, 1H), 7.15 (t, 3H), 6.84 (d, 2H), 6.54 (br, 2H), 4.00 (t, 2H), 3.83 (t, 2H), 3.21 (t, 2H), 3.05 (t, 2H), 2.45 (s, 3H). LRMS [M+H]=374.2
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:5][C:4]=1[CH2:23][S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].[N:37]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[C:27]1([S:24]([C:23]2[C:4]3[C:3](=[CH:22][CH:21]=[C:6]([O:7][CH2:8][CH2:9][O:10][S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:12])=[O:13])[CH:5]=3)[NH:2][N:37]=2)(=[O:25])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethanol (430 mL) in two portions and 1 N hydrochloric acid (200 mL) were added to toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-ethyl ester (6.5 g, 13 mmol). A solution of sodium nitrite (1.5 g, 22 mmol) in water was then added to the reaction mixture. The reaction was heated to aid in solubility. After stirring at ambient temperature for 2 hours, solid sodium carbonate was added to basic pH. The reaction mixture was stirred at ambient temperature for one hour. It was then solvent evaporated and partitioned in water and ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2% methanol in chloroform. Drying at 63° C. in vacuo yielded toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester a buff-colored foam (3.9 g, 59%); Mass Spectrum (+EI, [M+H]+) m/z 523. 1HNMR (500 MHz, DMSO-d6): δ14.09 (s, 1H), 8.76 (d, 1H, J=8.78 Hz), 8.52-8.55 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.64-7.74 (m, 3H), 7.55-7.63 (m, 2H), 7.50 (d, 1H, J=9.15 Hz), 7.27 (d, 2H, J=8.05 Hz), 7.14 (d, 1H, J=2.20 Hz), 6.94 (dd, 1H, J=9.15 Hz and 2.44 Hz), 4.32-4.34 (m, 2H), 4.18-4.20 (m, 2H), 2.25 ppm (s, 3H). Elemental Analysis for C26H22N2O6S2: Calcd: C, 59.76; H, 4.24; N, 5.36; Found: C, 59.69; H, 4.28; N, 5.14.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC1CCCC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 65.9 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 7.49 g (0.088 mol) of cyclopentylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C., then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 14.3 g (65.9%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(C2(Cc3ccccc3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 4b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 23 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product. Attempts to recrystallize the product failed. Sample was concentrated to give rac-3-benzyl-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a colorless glass. (Yield 0.17 g, 77.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16]C(C)(C)C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoate (5.38 g, 12.02 mmol) is dissolved in methylene chloride (100.0 mL). Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes. The reaction is sealed and stirred overnight at room temperature. The solvent is then evaporated to give 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH:15]=[CH:14][CH:13]=[C:12]2[C:16]([O:18]C)=O)=[CH:5][CH:4]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23].O.C(Cl)Cl>O1CCOCC1.[Cl-].[Na+].O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[NH:24][CH2:21][CH2:22][N:23]2[C:16](=[O:18])[C:12]2[N:11]([CH:15]=[CH:14][CH:13]=2)[CH2:10]3)=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(CO)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C1c2cccn2CC2(c3ccc(CO)cc3)NCCN12
Yield: 57.8 %

Procedure:
To a solution of methyl 1-{2-[4-(hydroxymethyl)phenyl]-2-oxoethyl}-1H-pyrrole-2-carboxylate (150 mg, 0.55 mmol) in 1,4-dioxane (25 mL) was added ethane-1,2-diamine (0.75 mL, 11 mmol). The solution was heated at reflux for 54 hours. The mixture was concentrated in vacuo to give a yellow oil, which was then portioned between water (30 mL) and CH2Cl2 (30 mL). Brine was added, and the organic layer was separated. The aqueous was further extracted with CH2Cl2 (2×30 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield a yellow solid, which was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0 to 10% methanol in EtOAc) to give 10a-[4-(hydroxymethyl)phenyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as an off-white solid (90 mg, yield: 57%). ESI-MI m/z [M+H]+ 283.9.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2.[CH2:16](I)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CCCCCC>[CH2:18]([O:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2)[CH:17]=[CH2:16]
Reactant: C=CCI
Reactant: Cc1ccc(O)c2c1=NC(=O)C(C)(C)C=2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(C)c2c1=CC(C)(C)C(=O)N=2
Yield: 92.6 %

Procedure:
Using 5-hydroxy-3,3,8-trimethylcarbostyril (2.0 g, 9.77 mmol), allyl iodide (1.72 g, 10.2 mmol), and potassium carbonate (3 g, 21.7 mmol), the procedure of Reference Example 41 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane). 2.2 g of the title compound was obtained as colorless flakes (92.0%).