Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br.CN(C)C=O>O>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: BrCCCBr
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(OCCCBr)ccc2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 12.6 g (0.076 mol) of 6-hydroxy-1,2,3,4-tetrahydro-2-quinolinone, 15.8 g (0.115 mol) of potassium carbonate (anhydrous and powdered), 46.5 g (0.23 mol) of 1,3-dibromopropane and 40 ml of N,N-dimethylformamide is stirred at room temperature for 20 hours. 200 ml of water and 100 ml of petroleum ether are added and, after stirring for 1 hour, the precipitate which has formed is filtered off with suction, washed with petroleum ether and dried.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[P:13]12(SP3(SP(SP(S3)(S1)=S)(=S)[S:15]2)=S)=[S:14]>C1(C)C=CC=CC=1>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([P:13](=[S:15])=[S:14])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCOc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCOc1ccc(P(=S)=S)cc1
Reaction time: 48 h

Procedure:
n-Pentyloxybenzene (Ia) and P4S10 (in a molar ratio of 10:1) were stirred for six hours at 150° C. under anhydrous conditions. The mixture was cooled, toluene was added, and the reaction flask was left for two days at 5° C. The resulting precipitate was recovered by filtration, washed with anhydrous ether and dried. The yield of product was 46% of theory; after recrystallization from chloroform/petroleum ether it melted at 144°-6° C. Its solubility in tetrahydrofuran was found to be 5 gms/100 ml at room temperature.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7](=[S:9])=[S:8].[OH-].[Na+].S(OC)(O[CH3:16])(=O)=O>O>[N:1]1([C:7]([S:9][CH3:16])=[S:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: S=C=S
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a stirred solution of morpholine (201 mL, 2295 mmol) in water (2 L) was added carbon disulfide (0.138 L, 2295.67 mmol) under nitrogen. Sodium hydroxide (96 g, 2410 mmol in solution in 1 L of water) was then added dropwise. The resulting mixture was stirred at room temperature for 1 h, then cooled to 5° C. with an ice bath and dimethyl sulfate (217 mL, 2295 mmol) was added dropwise. The mixture was stirred 1 hr at room temperature, the obtained solid was collected by filtration, washed with water (2×1 L) and dried under vacuum over phosphorus pentoxide at 50° C. to give methyl morpholine-4-carbodithioate (360 g, 88%). NMR Spectrum: (CDCl3): 2.68 (s, 3H), 3.71-3.84 (m, 4H), 4.02 (bs, 2H), 4.30 (bs, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1.N1C=CN=C1.[C:44]([Si:48](Cl)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOCC.CCCCCC>[Si:48]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 3.5 h

Procedure:
To a mixture of 3α, 12α-dihydroxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (10.2 g), imidazole (1.64 g) and 4-dimethylaminopyridine (0.256 g) in dimethylformamide (30 ml) is added tert-butylchlorodiphenylsilane (6.04 g) and the mixture stirred for about 3.5 hours and diluted with ether/hexane (1:1). The solution is washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 50% ether in hexane to give the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([OH:31])=[O:30])[CH2:28][O:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]([Cl:57])([Cl:56])[CH2:34][O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44](=[O:55])[C@@H:45]([NH:47][C:48](=[O:54])[C@@H:49](O)[CH:50]([CH3:52])[CH3:51])[CH3:46])[NH:39]1)=[O:37].C(N(CC)C(C)C)(C)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:56][C:33]([Cl:32])([Cl:57])[CH2:34][O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44](=[O:55])[C@@H:45]([NH:47][C:48](=[O:54])[C@@H:49]([O:30][C:29]([C:23]2(/[CH:22]=[CH:21]/[C:15]3[CH:14]=[C:13]4[C:18]([CH:19]=[CH:20][C:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])=[N:12]4)=[CH:17][CH:16]=3)[CH2:28][O:27][CH2:26][CH2:25][O:24]2)=[O:31])[CH:50]([CH3:51])[CH3:52])[CH3:46])[NH:39]1)=[O:37]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)COCCO3)cc2n1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Yield: 55.7 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carboxylic acid (50 mg, 0.1 mmol), [(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (44 mg, 0.1 mmol), N,N-diisopropylethylamine (32 mg, 0.043 mL, 0.25 mmol), 4-dimethylaminopyridine (6 mg, 0.05 mmol) and 2-methyl-6-nitrobenzoic anhydride (58 mg, 0.17 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated ammonium chloride solution, ice-cold saturated sodium hydrogen carbonate solution and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 1:3 to afford the title compound (47 mg, 55%) as a white solid and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 842.2/844.0 [M+H], Tr=3.25 and 3.31 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].O.[OH-].[Li+].S(OC)(O[CH3:18])=O>O1CCCC1>[Br:1][C:2]1[C:3]([O:11][CH3:18])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COS(=O)OC
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(C#N)cc1Br
Temperature: 75 °C
Yield: 83.9 %

Procedure:
To a solution 5-bromo-2-chloro-4-hydroxybenzonitrile (2, 29 g, 124 mmol) in tetrahydrofuran (500 mL) was added lithium hydroxide monohydrate (6.7 g, 161 mmol) and dimethyl sulfite (15.2 mL, 161 mmol). The resulting mixture was heated at 75° C. for 5 h, re-cooled to room temperature, and quenched with water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified on Biotage® purification apparatus (silica gel, 3 to 10% ethyl acetate in hexanes) to yield the title compound (26 g, 104 mmol, 85%) as a white solid.
Reaction SMILES: [CH3:1]NN.[CH:4]1([C:7]2[N:8](C)[N:9]=[C:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=23)[CH2:6][CH2:5]1>CO>[CH:4]1([C:7]2[C:11]3[CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:10]=3[N:9]([CH3:1])[N:8]=2)[CH2:6][CH2:5]1
Reactant: Cn1nc2c(c1C1CC1)CN(C(=O)OC(C)(C)C)CC2
Reactant: CNN
Solvent: CO
Product: Cn1nc(C2CC2)c2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
To a solution of C28 (100 g, 0.374 mol) in methanol (1.2 L) was added methylhydrazine (40% solution in water, 47.4 g, 0.411 mol). The reaction mixture was heated at reflux for 2 hours, then concentrated to dryness. Purification via silica gel chromatography (Gradient: 5% to 9% ethyl acetate in petroleum ether) provided a mixture of product C49 and tert-butyl 3-cyclopropyl-2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (C50). LCMS m/z 278.0 [M+H]+. Separation via supercritical fluid chromatography (Column: Chiral Technologies, Chiralcel OJ-H, 5 um; Eluent: 97:3 carbon dioxide/methanol) afforded the product C49 as the second-eluting isomer, isolated as a solid. NOE studies supported the indicated regiochemical assignment. Yield: 33 g, 120 mmol, 32%. 1H NMR (400 MHz, CDCl3) δ 4.40 (br s, 2H), 3.65-3.73 (br m, 2H), 3.65 (s, 3H), 2.57-2.64 (m, 2H), 1.68-1.76 (m, 1H), 1.49 (s, 9H), 0.77-0.89 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][CH:10]=O)=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1.CS(C1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=2[N:25]=1)(=O)=O>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]2[N:21]=[CH:22][C:23]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=3[N:25]=2)=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1
Reactant: COc1nc(S(C)(=O)=O)ccc1NC=O
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Product: COc1nc(S(C)(=O)=O)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 6 %

Procedure:
The title compound was prepared according to Example 40 using N-(2-methoxy-6-(methylsulfonyl)pyridin-3-yl)formamide (Preparation 73) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane. The residue was dissolved in EtOAc and washed with HCl (0.5 M, 10 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with DCM and dried under vacuum to give the title compound (3 mg, 6%).
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:32](=[O:40])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:7](=[O:31])[N:8]2[C:11](=[C:28]([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[NH:5]1)([OH:3])=O.C(Cl)(=O)[C:42]([Cl:44])=O.[N+](=CC(C1OC2C(C(=O)CC3C=CC=CC=3)(C(=O)N2C(=C(C)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N1)=O)=[N-].Cl>C1C=CC=CC=1.CN(C)C=O.CCOCC>[Cl:44][CH2:42][C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:32](=[O:40])[CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:7](=[O:31])[N:8]2[C:11](=[C:28]([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:5]1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Agent: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)C=[N+]=[N-])OC12
Agent: Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)CCl)OC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 1.774 g of diphenylmethyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 18 ml of benzene and 0.1 ml of N,N-dimethylformamide is added 0.43 ml of oxalyl chloride, and the mixture stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue (diphenylmethyl α-(3ξ-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate) is dissolved in 10 ml of methylene chloride and mixed with 15 ml of ether solution of diazomethane, which has been prepared from 1.5 g of nitrosomethylurea, under ice-cooling, and the mixture stirred for 30 minutes. To the resulting solution of diphenylmethyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is is added an ether solution of hydrogen chloride until the spot of diazoketone disappears, and the mixture concen rated under reduced pressure. The residue is purified by chromatography on 40 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.59 g of diphenylmethyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 84.7% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.CC1O[C:25]([C:27]2C=C[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)=[N:24]C=1CCO.Cl[C:46]1[CH:56]=[CH:55][C:49]([C:50]([N:52]([CH3:54])[CH3:53])=[O:51])=[CH:48][N:47]=1>>[CH3:53][N:52]([CH3:54])[C:50](=[O:51])[C:49]1[CH:55]=[CH:56][C:46]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:24]4[CH2:25][CH2:27][CH2:28][CH:29]4[CH3:30])[N:12]=3)=[CH:4][CH:3]=2)=[N:47][CH:48]=1
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Product: Cc1oc(-c2ccc(-c3ccc(C(=O)N(C)C)cn3)cc2)nc1CCN1CCCC1C

Procedure:
The titled compound is prepared substantially in accordance with the procedures of Example 4, Intermediate 13, and Example 75 using 2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3) and 6-chloro-N,N-dimethyl-nicotinamide [CAS: 54864-83-4].
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:34])[CH2:28][O:29][CH2:30][C:31]([O-:33])=[O:32])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[OH-:36].[Na+]>>[CH:1]([CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:31]([O-:33])(=[O:32])[CH2:30][O:29][CH2:28][C:27]([O-:34])=[O:36]
Reactant: O=C([O-])COCC(=O)NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: [OH-]
Agent: [Na+]
Product: NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Product: O=C([O-])COCC(=O)[O-]

Procedure:
A 1.02 gram (2.10 millimoles) sample of sodium {2-[6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetate (prepared as described in Example XIII) and 7.3 milliliters of 5 N aqueous NaOH is heated under reflux temperature for 1.5 hours to obtain 6-(4-benzhydrylpiperidino)hexanamine and diglycolate in the reaction mixture; the mixture is then diluted with 25 milliliters of water and extracted with ether. The ether solution is washed with aqueous NaCl, dried with Na2SO4, and concentrated to obtain as residue, 6-(4-benzhydrylpiperidino)hexanamine. To a solution of 0.685 gram (1.96 millimoles) of the thus prepared 6-(4-benzhydrylpiperidino)hexanamine in 14 milliliters of dichloromethane is added drop by drop during about 10 minutes, a warm solution of 0.227 gram (1.95 millimole) of diglycolic anhydride in 26 milliliters of dichloromethane. After the addition, the mixture is stirred at a temperature range of 25°-30° C. for two hours to obtain the desired {2-[ 6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetic acid; the latter is isolated by volatilization of the solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[CH:29](=O)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([N:26]([CH2:4][CH2:3][CH2:12][CH3:11])[CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])[CH2:30][CH2:31][CH3:32]
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Reactant: CCCC=O
Product: CCCCN(CCCC)CC(C)(C)c1nc(-c2ccc3cc(OC)ccc3c2)c(-c2ccncc2)[nH]1
Yield: 47 %

Procedure:
The title compound (12 mg, 47%) was prepared starting from the product of Example 2 and butyraldehyde using the method described in Example 25; MS(ES) m/e 485 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:47]=[C:17]2[N:18]([CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:47]=[C:17]2[N:18]([CH:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.37 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.23 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:36])[CH2:32][CH2:33][C:34]#[CH:35].CCN(CC)CC>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:35]=[C:34]([CH2:33][CH2:32][CH2:31][OH:36])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCCO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (800 mg), PdCl2(PPh3)2 (104.6 mg), CuI (34.1 mg), 4-pentyn-1-ol (0.17 mL), and Et3N (0.42 mL) in CHCl3 (14.9 mL) is stirred at room temperature overnight. Reaction condensed to remove CHCl3. The solvent is replaced with EtOH (15 mL) and additional Et3N (0.38 mL) is added to the reaction mixture. N2 is passed over the surface and the reaction is heated at 76° C. for 6 h, then allowed to cool to room temperature. Reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2. Product-containing fractions are combined, condensed, and recrystallized from hot acetonitrile to afford 408.9 mg (56%) of N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][CH:18]([F:20])[F:19])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:34][O:35][C:36](=[O:69])[NH:37][CH:38]([C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[C:49]1[NH:50][C:51]([C:54]2[CH:59]=[CH:58][C:57](B3OC(C)(C)C(C)(C)O3)=[CH:56][CH:55]=2)=[CH:52][N:53]=1)=[O:43])[CH:39]([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][CH:18]([F:20])[F:19])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:57]3[CH:58]=[CH:59][C:54]([C:51]4[NH:50][C:49]([CH:45]5[CH2:46][CH2:47][CH2:48][N:44]5[C:42](=[O:43])[CH:38]([NH:37][C:36]([O:35][CH3:34])=[O:69])[CH:39]([CH3:41])[CH3:40])=[N:53][CH:52]=4)=[CH:55][CH:56]=3)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC(COC(F)F)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC(COC(F)F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 29.5 %

Procedure:
(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (42 mg, 0.174 mmol), [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3 ,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (95 mg, 0.191 mmol), Pd(PPh3)4 (20 mg, 0.0174 mmol) and K2CO3 (2M in H2O, 0.191 mL, 0.383 mmol) were combined in 1,2-dimethoxyethane (2 mL). The mixture was degassed with bubbling N2 for 12 min then heated to 85° C. for 4 h. After cooling to RT, the reaction mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by HPLC to provide the title compound (42 mg, 30%). MS (ESI) m/z 819 [M+H]+.