Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)(O)[CH3:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:23]=[CH:24][CH:25]=[N:26][C:5]1=2.ClS(OC)(=O)=O.O.C(OCC)(=O)C>ClCCl>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]([C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4[N:23]=[CH:24][CH:25]=[N:26][C:5]=4[N:4]([CH2:3][O:2][CH3:1])[C:9]=3[CH:10]=2)=[CH2:15])[CH:18]=1
Reactant: COCN1c2cc(C(C)(O)c3cccnc3)ccc2Sc2nccnc21
Agent: COS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(c1cccnc1)c1ccc2c(c1)N(COC)c1nccnc1S2
Yield: 79.8 %

Procedure:
To a solution of 303 mg of 1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)1-(pyridin-3-yl)ethanol in dichloromethane was added in a nitrogen atmosphere 0.32 ml of methyl chlorosulfonate and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 230 mg of the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#N)#[N:2].Cl[C:14]1[C:19]([CH:20]2[CH2:22][CH2:21]2)=[C:18]([O:23][CH3:24])[N:17]=[C:16]([O:25][CH3:26])[N:15]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH:20]1([C:19]2[C:14]([CH:3]([C:4]3[CH:11]=[C:10]([CH3:12])[CH:9]=[C:6]([CH3:7])[CH:5]=3)[C:1]#[N:2])=[N:15][C:16]([O:25][CH3:26])=[N:17][C:18]=2[O:23][CH3:24])[CH2:22][CH2:21]1
Reactant: COc1nc(Cl)c(C2CC2)c(OC)n1
Reactant: Cc1cc(C#N)cc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(OC)c(C2CC2)c(C(C#N)c2cc(C)cc(C)c2)n1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
3-Cyanomethyl-5-methyl-benzonitrile (97 mg, 0.621 mmol) and 4-chloro-5-cyclopropyl-2,6-dimethoxy-pyrimidine (140 mg, 0.652 mmol, 1.05 eq.) were dissolved in 2 mL DMF. Cool the reaction flask to 0° C. NaH (60%, 51 mg, 1.24 mmol, 2 eq.) was added portionwise at 0° C. The reaction was stirred at 0° C., then warmed up to room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (67 mg, 33%). LC-MS shows 335.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.58 (s, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 5.82 (s, 1H), 4.0 (d, 6H), 2.4 (s, 3H), 1.43 (m, 1H), 1.09 (m, 2H), 0.64 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[N:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24](O)=[CH:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:24]2[CH:25]=[N:26][C:27]3[C:22]([CH:23]=2)=[N:21][C:20]([O:19][CH3:18])=[CH:29][CH:28]=3)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(O)cc2n1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.19 mmol, 1.0 eq) is added at room temperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol (37 mg, 0.19 mmol, 1.0 eq) in tetrahydrofuran (5 mL), followed by triphenylphosphine polymer-bound (3 mmol/g, 193 mg, 0.58 mmol, 3.0 eq) and diisopropyl azodicarboxylate (115 μL, 0.58 mmol, 3.0 eq). After 3 hours stirring at room temperature, the polymer-bound is filtered off and washed successively with tetrahydrofuran (5 mL), dichloromethane (5 mL) and methanol (5 mL). The resulting solution is concentrated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 4:1:0 to 0:9:1, v/v/v) to afford {1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (35 mg, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:14])[N:3]=1.C(N(CC)CC)C.[CH2:22]([O:24][CH2:25][C:26](Cl)=[O:27])[CH3:23]>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][C:26](=[O:27])[CH2:25][O:24][CH2:22][CH3:23])=[C:6]([NH:9][CH2:10][CH:11]([CH3:12])[CH3:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1cc(NCC(C)C)c(N)c(Cl)n1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(NCC(C)C)cc(C)nc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Anhydrous dichloromethane (750 ml) and 2-chloro-N4-(2-methylpropyl)-6-methylpyridin-3,4-diamine (18.84 g) were combined and cooled to 0° C. Triethylamine (12.9 ml) was added dropwise to the resulting mixture, and then ethoxyacetyl chloride (11.34 g) dissolved in anhydrous dichloromethane (50 ml) was added slowly to the resulting mixture, which turned dark. After two hours the dark mixture was allowed to warm to room temperature. TLC analysis of the reaction mixture indicated completion, and the solvent was removed under reduced pressure. The resulting yellow solid was dissolved in chloroform, and the resulting solution was washed with water. The organic layer was dried with magnesium sulfate and concentrated to a dark brown oil (27.75 g) under reduced pressure. NMR analysis of the oil indicated desired product of suitable purity for use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CC#N>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cc(O)cc(OCc2ccc(F)cc2)c1
Yield: 18.8 %

Procedure:
(3,5-Dihydroxy-phenyl)-acetic acid methyl ester (0.500 g, 2.75 mmol) in MeCN (5 ml) was treated with K2CO3 (0.095 g, 6.88 mmol) and 4-fluorobenzyl bromide (0.520 g, 2.75 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was directly purified by flash column chromatography (EtOAc:iso-hexane) to give [3-(4-fluoro-benzyloxy)-5-hydroxy-phenyl]-acetic acid methyl ester (0.15 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][OH:13].O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccnc2c1nc(CO)n2C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc1)n2C

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.50 g of 3,7-dimethyl-2-hydroxymethylimidazo[5,4-b]pyridine (prepared as described in Preparation 40), 3.94 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.11 ml of tributylphosphine, 2.14 g of 1,1'-(azodicarbonyl) dipiperidine and 30 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent, to give 1.11 g of the title compound, melting at 92-105° C. (softening).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)[N:9]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH3:18])[C@H:10]1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43].CN1CCOCC1>CN(C=O)C>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:42][NH:43][C:11](=[O:13])[C@@H:10]2[C@@H:14]([CH2:17][CH3:18])[CH2:15][CH2:16][N:9]2[CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:44]=[CH:45][CH:46]=1
Reactant: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)NCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline (0.50 g, 1.53 mmol), EDC (0.293 g, 1.53 mmol), HOBT (0.243 g, 1.53 mmol) and 3-chlorobenzylamine(0.187 mL, 1.53 mmol) were dissolved in DMF (5 mL), the pH adjusted to 7 with N-methyl-morpholine (0.51 mL, 4.6 mmol), and the reaction mixture stirred for 18 hours at ambient temperature. After removing the solvent in vacuo the residue was partitioned between EtOAc and 5% aqueous NaHCO3. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound after chromatography (SiO2, EtOAc:hexane, 2:3).
Reaction SMILES: [C:1]1([CH3:40])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:39])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[O:25])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:41][S:42](O)(=[O:44])=[O:43]>ClCCl>[C:35]1([CH3:38])[CH:36]=[CH:37][C:32]([S:29]([CH2:28][CH2:27][O:26][C:24](=[O:25])[CH2:23][O:22][C:17]2[CH:18]=[CH:19][C:20]([S:42]([Cl:41])(=[O:44])=[O:43])=[CH:21][C:16]=2[O:15][CH2:14][C:13]([O:12][CH2:11][CH2:10][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:40])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[O:39])(=[O:30])=[O:31])=[CH:33][CH:34]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccccc2OCC(=O)OCCS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)Cl)cc2OCC(=O)OCCS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
{2-[2-(Toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 37) (13 g, 22 mmole) was added to dichloromethane (30 mL), and cooled in an ice bath. Chlorosulfonic acid (10 mL) was slowly added, and the mixture was stirred at 0° C. for 2 hr., then at room temperature for 1 hr. Thereafter it was poured into crushed ice (200 g) with stirring. The precipitates were extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated, the residue was dried in vacuo to yield 17.3 g of {4-chlorosulfonyl-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 38).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
To a solution of 1H-indole-3-carbaldehyde (25.0g, 172 mmol) in tetrahydrofuran (500 mL) cooled to 0° C. with an ice-bath and under an inert atmosphere was slowly added sodium hydride (4.96 g, 207 mmol), such that the temperature of the mixture remained less that 5° C. After complete addition, the mixture was allowed to stir at 0° C. for 15 minutes. To the mixture was added benzyl bromide (35.4 g, 207 mmol). The ice bath was removed and the mixture was allowed to warm to room temperature over 1.5 hours. The mixture was then partitioned between brine and ethyl acetate. The layers were separated and the aqueous layer was extracted with two additional portions of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting red solids were dissolved in methylene chloride and the solution was filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure until a precipitate began to form. The product was crystallized out of the solution by the addition of an eight-fold volume of hexane. The red-tinted solid was isolated by vacuum filtration, and the process was repeated one additional time to give 1-benzyl-1H-indole-3-carbaldehyde (38.8 g, 96%) as an off-white powder. 1H NMR (400 MHz, CDCl3); δ 9.98 (s, 1H), 8.32 (m, 1H), 7.71 (s, 1H), 7.34 (m, 6H), 7.18 (m, 2H), 5.36 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)([O:3][CH3:4])=[O:2].[Al]>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:30])[CH3:31])[C:13]([O:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=NC2C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Agent: [Al]
Solvent: C1CCOC1
Product: COC(=O)C1NC2C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 23.0 g of diphenylmethyl α-(3-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-α-isopropylideneacetate in 480 ml of tetrahydrofuran containing 5% water is added aluminium amalgam prepared from 10 g of aluminium and 250 ml of 0.5% mercuric chloride and the mixture stirred at room temperature for 2 hours, dried on magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from a mixture of methylene chloride and ether (1:5) to yield 17.5 g of diphenylmethyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 76% yield.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22].C(O)C>C(#N)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[C:22]([CH2:21][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)OCCCNc1c(N)cnc2cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCO
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
7-Bromo-N4-(3-isopropoxypropyl)quinoline-3,4-diamine (45 g) was dissolved in acetonitrile (1.3 L) and triethylamine (19.4 mL). Ethoxyacetyl chloride (18.0 g) was added dropwise to the solution and the reaction was stirred for 16 hours. The solvent was removed under reduced pressure to afford a tan solid. The solid was added to a solution of ethanol (1 L) and triethylamine (77.5 mL) and heated at reflux for 4 hours. The solvent was removed under reduced pressure. Water was added to the solid residue and the crude product was recovered by filtration. Recrystallization from acetonitrile yielded 36.25 g of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline as a tan crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[Si:14]([O:21][CH2:22][C:23](=[O:25])[CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([OH:25])([CH3:24])[CH2:22][O:21][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
For a literature procedure to carry out a selective mono-lithiation of 2,5-dibromopyridine, see: Wang, X.; Rabbat, P.; O'Shea, P.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 2000, 41, 4335-4338. n-BuLi (3.17 mL, 5.07 mmol) was added to 2,5-dibromopyridine (1.00 g, 4.22 mmol) in toluene (49.7 mL) at −78° C. and stirred for 2 hours at −78° C. 1-{[tert-Butyl(dimethyl)silyl]oxy}propan-2-one (1.22 mL, 6.33 mmol) was added dropwise to the reaction mixture over 15 minutes. Upon addition, the reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl (2.00 mL) and the solvent was removed under reduced pressure. The resultant residue was diluted with dichloromethane (20.0 mL) and was partitioned with a saturated aqueous solution of NH4Cl (20.0 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate/hexanes) to yield 2-(5-bromopyridin-2-yl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol. MS APCI calc'd for C14H25BrNO2Si [M+H]+ 346. found 346 and 348.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:26]([OH:28])=[O:27])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2c(C(=O)O)cccc12
Temperature: -70 °C

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.28 g) in tetrahydrofuran (30 ml) was added butyl lithium (1.40 ml, 1.6 M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, and the mixture then stirred at the same temperature for 15 minutes. Gaseous carbon dioxide was introduced to the reaction mixture for 10 minutes and the temperature was raised to 0° C. The reaction mixture was poured into ice water (40 ml) and washed with diethylether (twice each with 40 ml). The aqueous layer was separated, after pH was adjusted to 4 with potassium dihydrogen phosphate, and extracted with ethyl acetate (twice each with 40 ml). The combined extracts was dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-1,2-benzisoxazole and 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-carboxy-1,2-benzisoxazole were obtained as a colorless oily mixture (0.31 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.[C:40](Cl)(=[O:42])[CH3:41].N1C=CC=CC=1>C(Cl)Cl>[C:40]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[CH:15]2[CH2:14][C:13](=[O:30])[NH:12][CH:11]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:39])[CH2:25][CH2:26]1)(=[O:42])[CH3:41]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 4 h
Yield: 8.2 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(4-piperidinyloxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (110 mg, 0.2 mmol), acetyl chloride (0.017 mL, 0.24 mmol) in DCM (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH2:32][CH3:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH2:32]([C:25]([CH3:31])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:33]
Reactant: CCOC(=O)C(C)(CC)CCCCBr
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CC)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
The procedure in Example 5 is followed but using 4,6-diphenyl-2-pyridinone (3 g), ethyl 6-bromo-2-ethyl-2-methylhexanoate (6.44 g) [prepared according to the method of K. E. MOELLER, Brenstoff-Chem., 47, 10 (1966)], silver carbonate (1.68 g) and dimethylformamide (110 cc). The reaction mixture is heated at 100° C. for 121 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1). (yellow oil)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.O.[OH-].[Na+].C(OCC)C>[C:18]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([CH3:17])[CH2:14][OH:15])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a cold (0° C.) mixture of 4.3 g (114 mmol) of lithium aluminum hydride in 100 ml of tetrahydrofuran, was added 10.74 g (47 mmol) of 2,2-diphenylpropanoic acid in portions. The resulting reaction mixture was allowed to warm to room temperature. When the reaction was substantially complete, as indicated by thin layer chromatography (TLC), the reaction mixture was diluted with approximately 10 ml of water, 8 ml of 1N sodium hydroxide and diethyl ether and stirred for ninety minutes at 0° C. The reaction mixture was then poured over celite, and washed sequentially with diethyl ether and eluted using a gradient eluent of 5-20% ethyl acetate in hexane. The fractions containing the desired compound were combined and concentrated in vacuo to provide 9.38 g of material.