Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C-:10]#[N:11].[K+].CS(C)=O>O>[C:10](#[N:11])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC#CCBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC#CCC#N

Procedure:
A mixture of 5 g. of 1-bromo-2-octyne, 7 g. of potassium cyanide and 35 ml. of dimethylsulfoxide is stirred and heated under nitrogen for about 2.5 hrs. at reflux temperature. The mixture is then poured into water and extracted with ether. The ether extract is washed with water, than with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 3-nonynenitrile. The thus obtained residue is mixed with 45 ml. of 25% hydrogen chloride in methanol containing 0.5 ml. of water while cooling in an ice bath. The ice is allowed to melt and the mixture is stirred for about 18 hrs., then is poured into water and extracted with ether. The ether extract is washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over sulfate, and evaporated under reduced pressure leaving a residue comprising methyl 3-nonynoate. A mixture of the thus obtained methyl 3-nonynoate, 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs., until the uptake of hydrogen practically ceases. The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising methyl 3-nonenoate.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[C:19]([CH3:40])=[C:18]3[CH3:41])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl.[NH2:43][NH2:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:43]([C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C@H:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=4)[CH3:11])=[O:14])=[CH:23][CH:22]=3)[C:18]([CH3:41])=[C:19]2[CH3:40])=[CH:30][CH:29]=1)=[O:38])[NH2:44]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Reactant: NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NN)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the mixture of (S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (0.11 g, 0.201 mmol), hydrazine hydrochloride (0.028 g, 0.402 mmol) and HATU (0.092 g, 0.24 mmol) in DCM (2 mL) was added DIEA (0.14 mL, 0.8 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed and the residue was purified by silica gel to obtain the title compound. ESI-MS (m/z): 559 [M+H]+.
Reaction SMILES: N#N.[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[CH2:8]([Li])[CH2:9][CH2:10][CH2:11]CC.C1(O)CC1>CN1C(=O)N(C)CCC1>[CH2:5]([CH:4]1[CH2:3][CH:7]1[OH:6])[CH2:11][CH2:10][C:9]#[CH:8]
Reactant: C1CCOC1
Reactant: [Li]CCCCCC
Agent: N#N
Agent: OC1CC1
Solvent: CN1CCCN(C)C1=O
Product: C#CCCCC1CC1O
Temperature: 0 °C
Reaction time: 0.07 h

Procedure:
To a 2-neck 15-mL flask equipped with a temperature probe, N2 inlet, and septum was added 1 g of 4 (7.28 mmol, 1.0 equiv) and 3.0 mL THF. The solution was cooled to an internal temperature of 0° C. with an ice bath. To this solution was added 2.95 mL of 33 wt % n-Hexyllithium (7.28 mmol, 1.0 equiv) slowly via syringe pump over 1 hour. Internal temperature rose to 6.8° C. and solution became yellow. In a separate 3-neck 100-mL flask equipped with a temperature probe, N2 inlet, and septum 0.82 g of lithium acetylide-ethylenediamine complex (8.01 mmol, 1.1 equiv) was slurried in 5.0 mL of DMPU at room temperature. To this room temperature slurry, the cold solution of the deprotonated cyclopropanol was transferred via cannula over 5 min. After the addition, the brown mixture was heated to an internal temperature of 52° C. with a heating mantle for 3 hours or until greater than 98% conversion was observed by GC. The brown mixture was cooled with an ice bath to 3° C. and then the ice bath was removed to prevent freezing. To this was slowly added 17.5 mL of 0.5 N HCl and an ice bath was applied to maintain an internal temperature below 21° C. The mixture was then diluted with 10 mL MTBE and 5 mL of water before transfer to a separatory funnel and removal of the aqueous layer. The aqueous layer was extracted once with 15 mL MTBE and then the combined organic layers were washed with 20 mL water followed by 20 mL brine. The organic layer was then concentrated in vacuo to afford 1.27 g of rac-5 as a yellow oil (72 wt %). 1H NMR (400 MHz, CDCl3) δ 3.24 (dt, 1H, J=2.6, 5.3 Hz), 2.25 (dt, 2H, J=2.6, 7.6 Hz), 1.96 (t, 1H, J=2.6 Hz), 1.92 (s, 1H, OH), 1.64 (pent, 2H, J=7.3 Hz), 1.38 (sext, 1H, J=6.9 Hz), 1.24 (sext, 1H, J=6.9 Hz), 0.93 (m, 1H), 0.72 (m, 1H), 0.35 (q, 1H, J=6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 84.49, 68.37, 52.45, 30.50, 27.74, 20.17, 18.01, 14.25; GC: HP1 (30 m×0.32 mm; 0.25 μm), 25 psi, 200° C. front inlet. 5 min @ 50° C., ramp 25° C./min to 250° C. then hold for 4 min, tr(4)=7.15 min, tr(rac-5)=6.72 min.
Reaction SMILES: CO.[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:13]([OH:32])[C:12]2=[O:33])=[CH:7][CH:6]=1)=O.[Cl-].[CH3:35][O:36][NH3+:37].C([O-])(=O)C.[Na+]>O>[OH:32][C:13]1[C:12](=[O:33])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:3]=[N:37][O:36][CH3:35])=[CH:10][CH:9]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]=1[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(C=O)cc3)C2c2ccccc2)cc1
Reactant: CO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=Cc1ccc(N2C(=O)C(O)=C(C(=O)c3ccc(OC)cc3)C2c2ccccc2)cc1
Yield: 2.9 %

Procedure:
To the 0.1M methanol solution of 1-(4-formylphenyl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydropyrrol-2-one (1 mL, 0.1 mmol) was added O-methylhydroxylammonium chloride (0.025 g, 0.3 mmol) and sodium acetate (0.025 g, 0.3 mmol). The mixture was stirred under reflux for 3 hr. Water (50 mL) was added to the mixture, which was then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitate was collected by filtration and dried to give 3-hydroxy-4-(4-methoxybenzoyl)-1-(4-methoxyiminomethylphenyl)-5-phenyl-1,5-dihydro-pyrrol-2-one (1.3 mg, 3%) as slightly yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C.O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:13][NH2:14]
Reactant: Clc1ccc2ccccc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc2ccccc2n1

Procedure:
To a solution of 2-chloroquinoline (15 g) in ethanol (150 ml) was added hydrazine hydrate (40 ml), the resulting solution was heated at reflux for 6 hours then diluted with water (400 ml) and extracted with diethyl ether (3×200 ml). The collected organic phase was washed with brine (300 ml), dried and concentrated under vacuum to afforg the title compound as a solid (13 g), 1H--NRM (DMSO); 4.29(s,2H), 6.83 (d,1H), 7.15(m,1H), 7.47(m,1H), 7.52(d, 1H), 7.62(dd, 1H), 7.86(d,1H), 8.05(s,1H)
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3C[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(C3CCCC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.NC1C=C([C:77]2[N:78]=[N:79][N:80]([CH2:82][O:83][C:84](=[O:89])[C:85]([CH3:88])([CH3:87])[CH3:86])[N:81]=2)C=CC=1.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH:20]1([C:18]2[C:17]3[CH:16]=[CH:29][CH:28]=[CH:27][C:26]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C:14](=[O:37])[N:13]([CH2:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([C:77]4[N:78]=[N:79][N:80]([CH2:82][O:83][C:84](=[O:89])[C:85]([CH3:87])([CH3:86])[CH3:88])[N:81]=4)[CH:9]=[CH:8][CH:7]=3)=[O:38])[N:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2cccc(N)c2)n1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(-c3nnn(COC(=O)C(C)(C)C)n3)c2)N=C(C2CCCC2)c2ccccc21

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and 2,2-dimethyl-propionic acid 5-(3-amino-phenyl)-tetrazol-2-ylmethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of 2,2-dimethyl-propionic acid 5-(3-{2-[5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-tetrazol-2-ylmethyl ester (Example 10, step a), according to the method of Example 10, step b. 1H NMR (d6-DMSO) 10.11 (1H, s), 8.36 (1H, s), 7.68-7.46 (5H, m), 7.22 (1H, m), 7.16 (1H, d), 6.95 (1H, br), 6.65 (1H, br), 4.64 (2H, m br), 4.35 (1H, m br), 4.00 (1H, m br), 3.00-2.80 (2H, m), 1.95-1.45 (9H, m), 1.40-1.00 (9H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 56.11; H, 7.00; N, 14.82%; C30H34N8O3.C7H17NO5.0.8CH3CO2H.2.2CH3OH requires C, 56.43; H, 7.31; N, 14.52%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]([NH2:30])([CH3:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[N:19]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:30][C:23]([C:20]3[N:19]=[C:18]([CH3:17])[O:22][N:21]=3)([CH3:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCCF)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)pyridine-2-carboxylic acid (example 146b) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (56 mg, 59%); MS (ESI, m/z): 427.2 (M+H+).
Reaction SMILES: C(O[C:9]1[CH:28]=[CH:27][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([OH:31])C>[Pd]>[OH:31][C:27]1[CH:28]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Reactant: CCO
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2O)CC1
Reaction time: 2 h

Procedure:
10% Palladium on carbon (0.75 g, 50% w/w) was added to a solution of tert-butyl 4-[4-(benzyloxy)phenoxy]piperidine-1-carboxylate (1.5 g) in ethanol (100 mL). The mixture was evacuated and purged with hydrogen twice and then stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through celite and the filter pad washed with ethanol. The filtrate was concentrated at reduced pressure to give tert-butyl 4-(hydroxyphenoxy)piperidine-1-carboxylate as a brown solid (1.24 g); NMR Spectrum: (CDCl3) 1.47 (s, 9H), 1.65-1.76 (m, 2H), 1.82-1.93 (m, 2H), 3.23-3.33 (m, 2H), 3.65-3.76 (m, 2H), 4.25-4.34 (m, 1H), 5.07 (s, 1H), 6.70-6.85 (m, 4H).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([OH:13])[CH:10]=[C:11]2[C:12]=1[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: C=CC(=C)C
Reactant: Cc1c(O)cccc1Cl
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1c(O)cc2c(c1Cl)CCC2(C)C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
437 g of isoprene stabilized with 1.3 g of phenothiazine were added dropwise in the course of 6 hours to a solution of 832 g of 3-chloro-2-methyl-phenol, 74.4 g of 85% strength phosphoric acid and 5.8 ml of water in 1.4 liters of o-dichlorobenzene at 110° C. To complete the reaction, stirring was continued overnight at 110° C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 296 g of 7-chloro-5-hydroxy-3,3,6-trimethyl-indan; boiling point: 161°-164° C./11 mm Hg; melting point: 109°-109.5° C. ##STR8##
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A suspension of 3 g (14.74 mmol) of 2-chloro-3,5-dinitropyridine in dioxane is admixed with 3.46 g (17.69 mmol) of tert-butyl 4-aminobutanoate hydrochloride and then with 4.21 ml (22.11 mmol) of triethylamine. The reaction mixture is stirred at 60° C. for 3 hours.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[N:33]1([CH2:38][C:39]2[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl>O1CCOCC1.CC(O)C>[CH3:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)[CH:40]=3)[N:7]=2)[CH:16]=1
Reactant: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Reactant: Nc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3ccnc(Nc4cccc(CN5CCCC5)c4)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Yield: 53.7 %

Procedure:
N-{3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mml), [3-(1-pyrrolidinylmethyl)phenyl]amine (46 mg, 0.26 mmol), and 4N HCl in dioxane (0.10 mL) were combined in i-PrOH (3 mL) in a procedure analogous to Example 67, Step B to afford the title compound as a yellow solid (70 mg, 53%). 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.55 (s, 1H), 8.71 (s, 1H), 8.47 (d, J=9.8 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.72-7.67 (m, 2H), 7.48-7.36 (m, 3H), 7.31-7.19 (m, 2H), 7.00-7.01 (m, 2H), 6.92 (d, J=7.5 Hz, 1H), 6.50 (d, J=5.6 Hz, 1H), 3.91 (s, 2H), 3.57 (s, 2H), 2.52-2.45 (m, 4H), 2.41 (s, 3H), 1.74-1.69 (m, 4H). ES-LC/MS m/z=600 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:35][CH2:36]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]
Reactant: CCNCC
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(C)c3C)c2cc1C#N
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (2.0 ml) and diethylamine (0.50 ml) to N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxyquinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea (80 mg), the mixture was heated at 60° C. for 6 hours. The reaction solution was allowed to cool, and the precipitated crystals were filtered out to obtain the title compound (32 mg) as light brown crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[S:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].F[B-](F)(F)F.[CH3:22][O+](C)C.O>C(Cl)Cl>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([S:16][CH3:22])=[N:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1CCCC(=S)N2
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CSC1=Nc2cccc(OC(C)=O)c2CCC1
Yield: 91.8 %

Procedure:
To a solution of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-thione (235 mg, 1.0 mmol) in 25 mL of CH2Cl2 was added at 0° 295 mg (2.0 mmol) of trimethyloxonium tetrafluoroborate. After stirring at room temperature for about 30 min. water was added and the CH2Cl2 layer was separated. Drying over Na2SO4 and removal of the solvent gave 229 mg of 4,5-dihydro-6-acetoxy-2-methylthio-3H-benzazepine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][C:17]([CH2:25][OH:26])([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:31]([O:26][CH2:25][C:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][C:15]([CH2:14][O:13][C:3]4[C:2]([Cl:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=4)([CH2:22]3)[CH2:16]1)[CH2:18]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c(OCC23CC4CC(C2)CC(CO[Si](C)(C)C(C)(C)C)(C4)C3)cc1F
Yield: 102 %

Procedure:
A solution of methyl 5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzoate (0.83 g, 2.17 mmol), tert-butylchlorodimethylsilane (0.36 g, 2.39 mmol), and imidazole (0.74 g, 10.90 mmol) in anhydrous dimethylformamide (12 mL) was stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), saturated ammonium chloride (2×50 mL) and brine (2×50 mL); dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (8:1 hexanes:ethyl acetate) to provide the title compound (1.10 g, quant): 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=7.6 Hz, 1H), 6.62 (d, J=12.1 Hz, 1H), 3.87 (s, 3H), 3.58 (s, 2H), 3.17 (s, 2H), 2.13-2.05 (m, 2H), 1.69-1.58 (m, 6H), 1.49-1.36 (m, 6H), 0.87 (s, 9H), −0.01 (s, 6H); MS (ES+) m/z 497.1, 499.1 (M+1).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])(C)C.[CH3:7][C:8]1([CH3:40])[CH2:13][CH:12]([O:14][C:15](=[O:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[O:25])[CH2:11][C:10]([CH3:39])([CH3:38])[NH:9]1>[Mo](=O)(=O)=O.CCCCCCCC>[CH2:15]([O:14][N:30]1[C:29]([CH3:36])([CH3:35])[CH2:28][CH:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([O:14][CH:12]2[CH2:13][C:8]([CH3:40])([CH3:7])[N:9]([O:5][CH2:1][CH2:4][CH2:8][CH2:13][CH2:12][CH2:11][CH2:10][CH3:38])[C:10]([CH3:39])([CH3:38])[CH2:11]2)=[O:37])[CH2:32][C:31]1([CH3:34])[CH3:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: CCCCCCCC
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 160.5 %

Procedure:
70% Aqueous t-butyl hydroperoxide (140 g, 1.09 mol) is added over a 6 hour period to a mixture of 75.4 g (0.157 mol) of bis(2,2,6,6-tetramethylpiperidin-4-yl)sebacate, 1.25 g (8.7 mmol) of molybdenum trioxide, and 570 ml of n-octane that has been heated to 115° C. under a nitrogen atmosphere. During the addition, the reaction is maintained at reflux. Water is collected in a Dean-Stark trap. Upon completion of the addition, the red reaction mixture is heated at reflux (95°-97° C.) for seven hours to discharge the red color. The molybdenum trioxide is removed by filtration. The yellow filtrate is stirred at ambient temperature for 30 minutes with 15 g of activated charcoal (DARCO) to remove some of the yellow color, and then concentrated at reduced pressure. The crude product is purified by flash chromatography on silica gel (100:3 heptane: ethyl acetate) to afford 92.9 g (80% yield) of the title compound, a colorless oil.