Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[O:19]=[C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:23][CH2:22][N:21]1[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([O-])=[O:36]>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][N:40]=[C:32]([N:21]2[CH2:22][CH2:23][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:20]2=[O:19])[CH:33]=1
Reactant: O=C([O-])c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Reactant: NCc1ccc(F)c(F)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Yield: 61 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 3,4-difluorobenzylamine to react with 2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinate, N-(3,4-difluorobenzyl)-2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 61% yield: mp 143-145° C.; 1H NMR (300 MHz, CDCl3) δ 8.64-8.53 (m, 2H), 8.36-8.35 (m, 1H), 7.68-7.63 (m, 1H), 7.40-7.38 (m, 1H), 7.29-7.02 (m, 6H), 4.57-4.52 (m, 4H), 4.06 (t, J=8.1 Hz, 2H), 3.53 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 157.2, 156.3, 153.0, 149.5, 148.4, 142.5, 137.1, 134.9, 123.9, 122.7, 122.1, 117.6, 117.3, 117.0, 116.8, 116.0, 108.9, 49.5, 43.0, 41.8, 41.5; MS (ES+) m/z 423.9 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][NH:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)[CH3:2].[ClH:25]>C(Cl)Cl>[ClH:25].[ClH:25].[NH2:10][C:9]1[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=1[CH:7]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:18])[N:6]1[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:23][CH3:24]
Reactant: CCN(CC)CCNC1c2ccccc2NC(=O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccccc1N

Procedure:
In 400 ml of methylene chloride was dissolved 26.7 g of 11-(2-diethylaminoethylamino)-5,11-dihydro-6H-dibenz[b,e]azepin-6-one, and dry hydrogen chloride gas was blown into the solution with stirring. The reaction solution was concentrated under reduced pressure and 100 ml of acetonitrile was added to the residue. The mixture was heated at reflux for an hour. After allowing the mixture to stand at room temperature, precipitated crystals were separated by filtration to give 28.02 g of 3-(2-aminophenyl)-2-(2-diethylaminoethyl)isoindolin-1-one dihydrochloride 0.25 hydrate (Compound 1').
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:11][CH2:10][C:9](=[O:12])[C:8]4[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=4[C:6]3=[O:17])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1ccc2c1C(=O)CCN(CCCCl)C2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc2c1C(=O)CCN(CCCN1CCN(c3ccc(F)cc3)CC1)C2=O

Procedure:
A suspension of Compound 6 (611 mg, 2.4 mmole), 1-(4-fluorophenyl)piperazine (649 mg, 3.6 mmole), potassium carbonate (498 mg, 3.6 mmole) and sodium iodide (720 mg, 4.8 mmole) in acetonitrile (30 ml) was refluxed for 38 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Reactant: c1nnn[nH]1
Product: CC1c2c(ccn2-c2nnn[nH]2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([C:27](O)=[O:28])=[CH:25][N:24]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:22]=2)[CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:27]([C:26]2[C:21]([CH:18]3[CH2:20][CH2:19]3)=[N:22][C:23]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=3)=[N:24][CH:25]=2)=[O:28])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
Reaction SMILES: [H-].[Ca+2].[H-].[CH3:4][C:5]1[CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=1/[CH:13]=[CH:14]/[C:15](/[CH3:24])=[CH:16]/[CH:17]=[CH:18]/[C:19](/[CH3:23])=[CH:20]/[CH:21]=O.Cl>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:4][C:5]1[CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=1/[CH:13]=[CH:14]/[C:15](/[CH3:24])=[CH:16]/[CH:17]=[CH:18]/[C:19](/[CH3:23])=[CH:20]/[CH:21]=[CH:21]/[CH:20]=[C:19](\[CH3:23])/[CH:18]=[CH:17]/[CH:16]=[C:15](\[CH3:24])/[CH:14]=[CH:13]/[C:6]1[C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH2:10][C:5]=1[CH3:4]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Ca+2]
Solvent: C1CCOC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution was prepared by dissolving titanium tetrachloride (1.10 ml, 10.0 mmol) in 25 ml tetrahydrofuran under an inert atmosphere. Calcium hydride (420 mg, 10.0 mmol) was added, and the resulting solution was stirred for two hours at room temperature. A solution of retinal, (1.42 gm, 5.0 mmol) in 5 ml dry tetrahydrofuran was then added, and the reaction was refluxed for three hours. After this, the solution was poured into 50 ml 2 N aqueous hydrochloric acid, and was extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by solvent removal at the rotary evaporator. The residue was further purified by chromatography on silica gel. Elution with hexane gave 1.0 gm (75%) beta-carotene, identified by thin-layer chromatographic comparison with an authentic sample, and by its melting point, mp 180°-182°.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][O:6]C(C)(C)[N:4]1C(OC(C)(C)C)=O)#[CH:2].[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>CO>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:4][C@H:3]([C:1]#[CH:2])[CH2:7][OH:6]
Reactant: C#C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C#C[C@@H](N)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-tert-butyl 4-ethynyl-2,2-dimethyloxazolidine-3-carboxylate (680 mg) (Tetrahedron 1996, 52, 11215.) in methanol (20 mL) was added trifluoroacetic acid (0.23 mL). The reaction mixture was stirred at room temperature for 4 hr and concentrated under reduced pressure to give the title compound (623 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:11]([F:18])([F:17])[C:12]([O:14]CC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[F:18][C:11]1([F:17])[CH:10]([O:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:12]1=[O:14]
Reactant: CCOC(=O)C(F)(F)C(CNC(=O)OC(C)(C)C)OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C(=O)C2(F)F)cc1
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of ethyl 4-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}butanoate (44.8 g) in ethyl acetate (50 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL), and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically distilled twice with toluene. The obtained mixture was dissolved in acetonitrile (20 mL), triethylamine (15.6 g) was added, and the mixture was stirred for 3 hr. Di-tert-butyl bicarbonate (33.6 g) and 4-dimethylaminopyridine (3.76 g) were added at room temperature and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow oil (yield 32.0 g, 80%).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[C:12]([O:18]C)[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B(Br)(Br)Br>>[CH3:9][C:2]([C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([CH:11]=1)[OH:18])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1cc(OC)cc(OC)c1
Agent: BrB(Br)Br
Product: CCCCCCC(C)(C)c1cc(O)cc(O)c1

Procedure:
The process of claim 1, said process comprising reacting 2,6-dimethoxyphenol with 1,1-dimethyl-1-heptanol in the presence of methanesulfonic acid to provide 1-hydroxy-2,6-dimethoxy-4-(1,1-dimethylheptyl)benzene; reacting said 1-hydroxy-2,6-dimethoxy-4-(1,1-dimethylheptyl)benzene with a halogenated disubstituted phosphite to provide a 2,6-dimethoxy-4-(1,1-dimethylheptyl)phenyl disubstituted phosphate; reacting said 2,6-dimethoxy-4-(1,1-dimethylheptyl)phenyl disubstituted phosphate with an alkali metal to afford 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene; reacting said 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene with boron tribromide to provide 5-(1,1-dimethylheptyl)-resorcinol, and recovering said 5-(1,1-dimethylheptyl)-resorcinol therefrom.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[CH:7]1.[I-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl.C(OCC)(=O)C.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14]4[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=4[CH:8]=[CH:7]3)[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C1CCCc2c1ccn2CCCCCl
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CCCc2c1ccn2CCCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of 1-(4-Chlorobutyl)-1,5,6,7-tetrahydroindol-4-one (600 mg) from step 1 and sodium iodide (438 mg) in acetonitrile (10 mL) was heated at reflux for 6 hours. (3,4-Dichlorophenyl)piperazine (581 mg) and potassium carbonate (367 mg) was then added and reflux continued for 16 h. TLC (ethyl acetate:dichloromethane 1:1) showed complete reaction. The reaction was poured into ice cold water (50 mL) and stirred for 0.5 hours. An oil separated out and was isolated from the mixture. The oil was dissolved with dichloromethane (15 mL), washed with water and brine, then dried with sodium sulfate, filtered and the solvent removed under vacuum to yield the title compound as an oil (970 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]
Reactant: Oc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A solution of 2,4-difluorophenol (5.39 g, 41.4 mmol) in dimethylformamide (34.5 mL) at 10° C. under nitrogen was treated portionwise with sodium hydride (1.657 g, 41.4 mmol), stirred for 15 minutes and treated portionwise with 4-fluoro-3-nitrobenzenesulfonamide (2.28 g, 10.36 mmol). The solution was stirred at ambient temperature for 1.5 hours, diluted into ethyl acetate and carefully quenched with 0.5 M HCl to a constant pH of 6. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. The residue was triturated in 3:1 hexane/ethyl acetate to afford the title compound (3.24 g, 95%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH:12]=[CH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])C.C(Cl)(Cl)Cl>O1CCOC1>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH2:12][C@@H:11]1[CH:30]1[O:33][CH2:34][CH2:35][O:32]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C=CC(=O)O1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCO1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 94 %

Procedure:
A solution containing 228 mg (0.998 mmol) compound (2a) and 18.0 mg (0.998 mmol) benzophenone in 200 mL [1,3]-dioxolane was irradiated at 20° C. for 5 hours according to the general procedure. Column chromatography (silica gel 35 g, ethyl acetate in hexanes 30%) gave compound (3a) (285 mg, 94%) as a colorless solid, Rf=0.35, [α]25D 18.3°, c 1.3, CHCl3, IR (neat) 2953, 2857, 1778, 1125 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 0.05 (s, 6H), 0.87 (s, 9H), 2.45 (dd, 1H, J=4.2 Hz, J=17.7 Hz), 2.68 (d, 1H, J=17.7 Hz), 2.72-2.79 (m, 1H), 3.65 (dd, 1H, J=2.7 Hz, J=11.4 Hz), 3.86-3.91 (m, 3H), 3.97-4.01 (m, 2H), 4.50 (mc, 1H), 4.88 (d, 1H, J=3.6 Hz). 13C-NMR (75.4 MHz, CDCl3, Dept) δ: 5.52 (+), 18.18 (quat), 25.77 (+), 30.12 (−), 39.67 (+), 64.71 (−), 65.36 (−), 65.47 (−), 80.24 (+), 103.94 (+), 176.55 (quat). C14H26O5Si; Exact Mass: 302.15; Mol. Wt.: 302.44; C, 55.60, H, 8.67, O, 26.45, Si, 9.29.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37]>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN(C)CCCN
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNCCCN(C)C)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and N1,N1-dimethyl-propane-1,3-diamine.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[C:14]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]>C(O)CC(C)C>[C:14]([N:18]1[CH2:23][CH2:22][N:21]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Product: CC(C)(C)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-tert-butylpiperazine (72.5 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 and worked up; yield: 42 mg (28%), crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:33])[C:18](=[O:20])[CH2:17][O:16][C:12]3[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=3)[CH2:28][CH2:27]2)[CH2:23][CH2:24]1
Reactant: CNC1CCN(CC2CC2)CC1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Compound 9 (100 mg), 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine (56.6 mg) and triethylamine (234 μL) were suspended in acetonitrile (2 mL). While the suspension was cooled with ice, a 50% propane phosphonic acid anhydride ethyl acetate solution (273 mg) was added portionwise. The equipment used to add the 50% propane phosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (0.5 mL) and was stirred at room temperature (20 to 30° C.) overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=30:1) to give 79 mg (52% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20]OS(C)(=O)=O)[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][N:30]3[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]3)[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: OC1CCN(Cc2cc(-c3ccc(OCc4ccccc4)cc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonic acid-3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.42 mmol), 4-hydroxypiperidine (64 mg, 0.63 mmol), potassium carbonate (87 mg, 0.63 mmol), and TBAI (96 mg, 0.26 mmol) were placed in 10 ml of DMF and stirred at room temperature overnight. The completion of the reaction was confirmed by LC, and then a crude solid compound obtained from distillation of the DMF under reduced pressure was extracted with ethyl acetate and water. The ethyl acetate was distilled off under reduced pressure to obtain a white solid compound. The compound was recrystallized from methylene chloride:MeOH (9:1) to obtain 1-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidin-4-ol as a white solid compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])CCC.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:20]3([OH:23])[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[CH:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2sccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2cc3cc(Cl)ccc3s2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A solution of 0.300 gm (1.78 mMol) 5-chlorobenzothiophene in 20 mL tetrahydrofuran was cooled to -78° C. To the cooled solution was then added 1.27 mL (1.78 mMol) n-butyllithium (1.2M in tetrahydrofuran) and the reaction mixture stirred for 1 hour after the addition was complete. To this solution was added 0.218 mL (1.78 mMol) 1-methyl-4-piperidone and the reaction mixture was allowed to warm to 0° C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned by the addition of hexane/diethyl ether. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to provide 0.34 gm of a tan solid. This residue was subjected to silica gel chromatography, eluting with chloroform containing 5% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.34 gm (68%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:25])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.C([O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])(=O)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.CC#N.O.O>[Br:25][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:31](=[O:32])[C@@H:30]([OH:29])[CH3:34])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O[C@@H](C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
(R)-tert-Butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.200 g, 0.487 mmol; Example 98, Step A), (S)-2-acetoxypropanoic acid (0.386 g, 2.92 mmol), BOP-Cl (0.745 g, 2.92 mmol), and triethylamine (0.679 mL, 4.87 mmol) were placed in DCM (6 mL) and stirred at room temperature for 18 hours. 3M aqueous LiOH (6 mL) was then added. The reaction was stirred for 10 minutes, poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95 CH3CN/water) to give tert-butyl (R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 51% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([OH:14])=[O:13].B(Br)(Br)Br.Cl[CH2:20]Cl>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([O:14][CH3:20])=[O:13]
Reactant: COc1cc(F)c(CC(=O)O)c(F)c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: COC(=O)Cc1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2,6-difluoro-4-methoxyphenyl)acetic acid (1.50 g, 7.42 mmol) in 20 ml anhydrous dichloromethane at 0° C. was added a solution of boron tribromide (4.29 ml, 44.5 mmol) in 10 ml anhydrous dichloromethane. The cooling bath was removed and the mixture allowed to warm to RT for 2 hours. The reaction was diluted with 20 ml anhydrous methanol, and stirred for 30 minutes. The mixture was concentrated under reduced pressure, and the residue purified by column chromatography on silica gel, (Biotage column, 50 g) using a gradient eluent of 0-30% ethyl acetate in hexanes (700 ml) to afford the title compound. 1H NMR (CDCl3): δ 6.30 (d, J=8.3 Hz, 2H), 6.12 (br, 1H), 3.76 (s, 3H), 3.63 (s, 2H).