Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:16]4[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=4)=[CH:11][CH:12]=3)[C:7]3([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]3)[C:6]=2[CH:5]=[C:4]([O:29]C)[CH:3]=1.C(Cl)Cl>>[NH2:28][C:24]1[O:25][CH2:26][CH2:27][C:7]2([N:23]=1)[C:6]1[CH:5]=[C:4]([OH:29])[CH:3]=[C:2]([F:1])[C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:12]=1
Reactant: COc1cc(F)c2c(c1)C1(CCOC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Solvent: ClCCl
Product: NC1=NC2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a suspension of 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (2.178 g, 5.32 mmol) in DCM (43 mL) boron tribromide (1.509 mL, 15.96 mmol) was added dropwise at RT. The mixture was stirred 2 hrs at RT, the mixture was cooled to 0° C. and quenched by addition of 5 ml of methanol dropwise. The resulting white suspension was stirred for 20 min at 0° C., then sat. aq. NaHCO3 (˜5 ml) was added followed by addition of 25% aq. ammonia (˜15 ml). The mixture was stirred for 30 min, then DCM was removed in a stream of nitrogen. The mixture was diluted with water (10 ml) and 25% ammonia (10 ml) and filtered. The white solid was washed with water twice, then dried for 3 hrs on air, then in vacuo overnight to give 2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2′-ol (2.08 g, 5.26 mmol, 99% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>O1CCCC1.O>[C:28]([O:27][C:25](=[O:26])[CH2:24][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CC(=O)OC(C)(C)C)CCOCC1
Temperature: -35 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Diisopropylamine (1.28 mL, 9.16 mmol) was diluted with tetrahydrofuran (2 mL) and cooled to −78° C. n-Butyllithium (2.5 M, 3.66 mL, 9.16 mmol) was added dropwise, and the solution was allowed to stir for 1 h. Methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 7.63 mmol) was added as a solution in tetrahydrofuran (1.5 mL) at −78° C. The mixture was allowed to warm to −35° C. and stirred for 1 h. tert-Butyl bromoacetate (1.58 mL, 10.7 mmol) was added neat at −35° C. The mixture was allowed to warm to 0° C. and stirred for 2 h. The mixture was stirred at rt overnight. Water was added at 0° C. and the mixture extracted with ethyl acetate. The organic phase was washed with brine, and dried over sodium sulfate. The crude product was purified by flash chromatography (Biotage Flash 40M, 6:1 hexane/ethyl acetate) to afford methyl 4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.12 g, 56%). LC-MS ret. time 2.47 min, m/z 258.7 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 9H), 1.52-1.61 (m, 2H), 2.00-2.07 (m, 2H), 2.50 (s, 2H), 3.52-3.60 (m, 2H), 3.70 (s, 3H), 3.71-3.77 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12]C)[CH2:10]C)=[CH:4][CH:3]=1.Cl.ClCCN(C)C>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCOc1ccc(Br)cc1
Agent: CN(C)CCCl
Agent: Cl
Product: CN(C)CCOc1ccc(Br)cc1

Procedure:
Prepared according to the procedure analogous to that described above for [2-(4-Bromo-phenoxy)-ethyl]-diethyl-amine, except using (2-chloro-ethyl)-dimethylamine hydrochloride.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH2:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1C=CC=CC=1>[C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC(=O)OOC(C)(N)CC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)OOC(C)(CC)NS(C)(=O)=O
Yield: 67.5 %

Procedure:
To a solution of 15.9 g of ethyl-β-amino-β-ethoxy acrylate in 60 ml of benzene was added 10.3 g of triethylamine, and a solution of 11.5 g of methanesulfonyl chloride in 40 ml of benzene was dropped thereinto with stirring. After the dropping, the resulting mixture was stirred at room temperature for 5 hours. The crystals formed were separated. The filtrate was concentrated under reduced pressure and the concentrated residue crystallized by cooling. When the crystals were washed with n-hexane and dried, 16 g of prismatic crystals of a melting point of 103° to 104° C. was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC.CCCCCCC>[CH2:23]([C:24]1[CH:23]=[C:23]([C:24]([CH:8]2[C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)([C:5]2[CH:17]=[CH:16][CH:15]=[CH:7][CH:6]=2)[C:25]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:26]=2)[CH2:26][CH:25]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCCC
Product: CCCCC1=CCC(C(c2ccccc2)(c2ccccc2)C2c3cc(C(C)(C)C)ccc3-c3ccc(C(C)(C)C)cc32)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 171.2 %

Procedure:
To 2,7-di-tert-butylfluorene (15 g, 54 mmol) dissolved in Et2O (100 mL) was added n-BuLi (5.8 mL of 10 M in hexanes, 58 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The anion solution was added to 2-butyl-6,6-diphenylpentafulvene (F-1) (16 g, 56 mmol) dissolved in Et2O (100 mL) at −78° C. in 5 minutes. The mixture was warmed to room temperature and stirred for 2 days. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with Et2O. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave a viscous oil. The oil was stirred in heptane to give a white solid. The solid was filtered, washed with heptane and dried under vacuum. A mixture of isomers for the desired product (18.7 g, 61.3% yield) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:23])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of (5-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 100.3) (10.7 g, 51.4 mmol), NBS (10.1 g, 56.7 mmol, 1.1 equiv), AIBN (843 mg, 5.14 mmol, 0.1 equiv) in CCl4 (500 mL) was stirred for 1 h at relfux. NBS (1.8 g, 10.1 mmol, 0.2 equiv) was added and the mixture was stirred at reflux for additional 30 min. The reaction mixture was filtered hot and the filtrate was concentrated. Trituration of the residue in CH3CN afforded of 12.88 g of impure (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (intermediate 100.2). (R)-3-Hydroxypyrrolidine (181 mg, 2.1 mmol, 1.2 equiv) was added to a mixture of intermediate 100.2 (500 mg, 1.75 mmol) and Cs2CO3 (684 mg, 2.1 mmol, 1.2 equiv) in DMF (5 ml). The reaction mixture was stirred for 24 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 (150 mL) and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) to afford 212 mg of the title compound as a white solid. Title compound: ESI-MS: 294.3 [M+H]+; tR=1.95 min (System 1); TLC: Rf=0.14 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[C:27]([O:31][CH:32]1[CH2:37][C:36]([CH3:39])([CH3:38])[N:35]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:34]([CH3:50])([CH3:49])[CH2:33]1)(=[O:30])[CH:28]=[CH2:29].CC(C)([O-])C.[K+]>[Pd].O1CCCC1>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH2:29][CH2:28][C:27]([O:31][CH:32]2[CH2:33][C:34]([CH3:49])([CH3:50])[N:35]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]([CH3:38])([CH3:39])[CH2:37]2)=[O:30])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1(C)C
Reaction time: 120 h
Yield: 35.5 %

Procedure:
A mixture of 19.2 grams (69.6 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 0.8 grams of 10% palladium on carbon, 2.0 grams of anhydrous magnesium sulfate and 100 ml of anhydrous tetrahydrofuran is hydrogenated (48 psi, 25° C.) on a Parr apparatus for three hours. Solids are then removed by filtration. To the filtrate are added 19.7 grams (58.0 mmol) of 1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate, 0.8 gram of potassium tert-butoxide and 40 ml of tetrahydrofuran. The reaction mixture is purged with nitrogen, stoppered and allowed to stand at 25° C. for five days. The mixture is then diluted with diethyl ether (200 ml), and washed successively with 1N hydrochloric acid (2×75 ml) and saturated sodium bicarbonate solution (200) ml), and then dried over anhydrous magnesium sulfate and concentrated to a pink residue. Purification by flash chromatography on silica gel (4:1, heptane:ethyl acetate) affords 12.7 grams (35% yield) of the title compound as a colorless syrup.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH3:8][O:9][C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13](B(O)O)=[CH:12][N:11]=1.O.C([O-])(O)=O.[Na+]>COCCOC.ClCCl>[CH3:8][O:9][C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:2]2[N:3]=[C:4]([CH3:7])[S:5][CH:6]=2)=[CH:12][N:11]=1
Reactant: Cc1nc(Br)cs1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ncc(-c2csc(C)n2)c(OC)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4-bromo-2-methyl-1,3-thiazole (commercially available from Frontier, 300 mg, 1.685 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (97 mg, 0.084 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 651 mg, 3.54 mmol) and 1M/H2O sol. of NaHCO3 (4.60 ml, 4.60 mmol) were added thereto. The reaction mixture was heated at 90° C. for 2.5 h and left at room temperature overnight. The mixture was then diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic layer was separated through an hydrophobic frit and concentrated. The obtained crude was purified by flash chromatography eluting with Cyclohexane/AcOEt 8/2. 290 mg of the title compound were isolated as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH:5]2O.O.[NH2:14]N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([OH:11])=[N:6][N:14]=[CH:5]2
Reactant: NN
Reactant: O=C1NC(O)c2cc(Br)ccc21
Solvent: O
Product: Oc1nncc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.4 %

Procedure:
A mixture of 5-bromo-3-hydroxyisoindolin-1-one (16, 17.0 g, 75 mmol), and hydrazine, monohydrate (60 mL, 1193 mmol) was stirred at room temperature for 15 h, after which a white solid precipitated out (M+1=225, 227). The mixture was diluted with 100 mL H2O, neutralized with conc. HCl to a PH of about 7. The precipitate was filtrated and washed with 100 mL H2O. The solid was collected, azeotropically dried with toluene (3×50 mL) and further dried in a vacuum oven at 45° C. for 15 h, to yield 6-bromophthalazin-1-ol 17 (16.1 g). Found MS (ES+): 225, 227 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=O)[O:21]C3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]([C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36]>>[CH3:33][O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)=[O:21])[CH2:39][CH2:38]1)=[O:36]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: COC(=O)C1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-cyclohexane-carboxylic acid methyl ester was prepared starting from intermediate M and trans-4-amino-cyclohexane carboxylic acid methyl ester. MS calcd. for C25H27ClN3O4 [(M+H)+] 468.2, obsd. 468.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH2:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([NH:4][CH2:3][CH2:2][OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: BrCc1ccccc1
Product: OCCNCc1ccccc1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[O:53][CH:52](CO)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH:24]([CH2:52][OH:53])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OCC1CNCCO1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCOC(CO)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and morpholin-2-ylmethanol and isolated as light-yellow gum (11.8 mg, 60%). MS(m/e): 417.5 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[N:31]=[C:30]([CH2:32][N:1]3[CH:2]([C:11]4[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cccn2)n1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 393.10 g/mol.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[N:63][C:64]([N:67]3[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]3)=[CH:65][CH:66]=2)[C:50]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:73])[C:51]([C:61]1[CH:62]=[N:63][C:64]([N:67]3[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]3)=[CH:65][CH:66]=1)=[N:52]2
Reactant: Cc1c(-c2ccc(N3CCCCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCCCC3)nc2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 5-morpholinopyridin-3-amine (0.058 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)quinoline (0.1 g, 0.27 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (2.7 mL) at 100° C. for 23.3 h. The crude product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield the desired product 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.43-8.47 (2H, m), 7.86 (1H, dd, J=8.9, 2.6 Hz), 7.79 (1H, d, J=2.4 Hz), 7.56-7.61 (2H, m), 7.37 (1H, ddd, J=12.5, 9.5, 2.7 Hz), 6.93 (1H, d, J=8.8 Hz), 6.55 (1H, t, J=2.3 Hz), 3.66-3.74 (4H, m), 3.59-3.66 (4H, m), 3.04-3.11 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=517.2 (M+1).
Reaction SMILES: C([C:4]12[CH2:19][CH2:18][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)C=C.ClC1C=CC=[C:23]([C:27]([O:29]O)=O)[CH:22]=1>CCOCC.C1C=CC=CC=1>[O:29]1[CH2:27][CH:23]1[CH2:22][C:6]1[C:5]2[CH:4]3[CH2:19][CH2:18][CH:11]([C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C=CCC12CCC(c3ccccc31)c1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1ccc2c(c1)C1CCC2c2c(CC3CO3)cccc21

Procedure:
A solution of 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracene (1.1 g) and m-chloroperbenzoic acid (1.6 g) in ether was stirred at room temperature for 5 days. The solution was diluted with benzene, washed with aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-β,γ-epoxypropyl-9,10-dihydro-9,10-ethanoanthracene as an oil, I.R., 3070, 3040, 3020, 2860, 1263, 1140, 1033, 830, 760, 680, 630 cm-1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:23].[CH3:24][N:25]=[C:26]=[S:27].C(N(CC)CC)C.C1COCC1>O.C(Cl)(Cl)Cl>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][NH:2][C:26](=[S:27])[NH:25][CH3:24])[C:6]([CH3:23])=[N:7][C:8]=2[CH:13]=1
Reactant: CN=C=S
Reactant: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(=S)NCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
1-(2-Aminoethyl)-5-(benzoxazol-2-yl)-2-methylbenzimidazole hydrochloride (see Working Example 56) (0.20 g, 0.6 mmol), methyl isothiocyanate (0.17 g, 0.6 mmol), triethylamine (0.13 g, 13 mmol) and THF (2 mL) were added together, and stirred for 1 hour at room temperature. After cooling, chloroform and water were added and extraction was carried out. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The solid obtained was separated by filtration and dried to yield the title compound (0.08 g, 40% yield) as white crystals.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.[CH3:12][SH:13]>C(N(CC)CC)C>[CH3:12][S:13][C:6]([CH3:7])([CH3:8])[CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:11][C:9]1=[O:10]
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Reactant: CS
Solvent: CCN(CC)CC
Product: CSC(C)(C)C1CCC(C)CC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.2 g of pulegone are treated with 0.5 ml of triethylamine and cooled to ca 0° by means of an ice-common salt mixture. With stirring, methyl mercaptan in excess is condensed into the mixture and, after condensation of 200% of the calculated amount, the mixture is transferred into an autoclave. After standing overnight at room temperature, the reaction mixture is heated to 50° and, after cooling of the autoclave, the reaction product immediately distilled in vacuum. 9.8 g of 8-methylthio-p-menthan-3-one are obtained as a clear liquid with pleasant odour reminiscent of peppermint, geranium and caraway, boiling point 72°-73°/0.15 mm Hg, nD20 1.4982. The yield amounts to 73% of the theory based on reacted pulegone. The two stereoisomeric compounds 8-methylthio-cis-p-menthan-3-one and 8-methylthio-trans-p-menthan-3-one obtained can be separated gas-chromatographically.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.[CH:22]([N-]C(C)C)(C)C.[Li+].IC.O>C1COCC1.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)=[N:11][O:12][C:8]=2[CH:7]([CH3:22])[CH2:6]1
Reactant: O=C1c2c(-c3ccc(F)cc3)noc2CCC1CCCCl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(CCCCl)C(=O)c2c(-c3ccc(F)cc3)noc21
Temperature: -78 °C

Procedure:
In 140 ml anhydrous THF was dissolved 4.20 g 5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 14.0 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stirred for 10 minutes at -78° C. and 1.30 ml iodomethane was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted two times with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product as an oil. Column chromatography on silica gel (start eluting with 10% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) afforded 4.00 g of 5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-7-methyl-1,2-benzisoxazol-4(5H)-one as an oil.
Reaction SMILES: [CH3:1][O:2]C1C=CC(C2SCCS2)=CC=1.COC1C=C(C=CC=1)C(Cl)Cl.CO[C:27]1[CH:28]=[C:29]([C:33]([Cl:36])([Cl:35])[Cl:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:1][O:2][C:32]1[CH:27]=[CH:28][C:29]([C:33]([Cl:34])([Cl:35])[Cl:36])=[CH:30][CH:31]=1
Reactant: COc1ccc(C2SCCS2)cc1
Reactant: COc1cccc(C(Cl)(Cl)Cl)c1
Agent: COc1cccc(C(Cl)Cl)c1
Product: COc1ccc(C(Cl)(Cl)Cl)cc1

Procedure:
5.8 gm (0.0274 moles) of the dithiolane of Example 4 was reacted following the procedure of Example 6 to give 5.01 gm of a 3.8:1 mixture of 3-methoxybenzaldichloride and 3-methoxybenzotrichloride (b.p. 83°-84° C. at 0.3 mm/Hg). NMR and GC/MS Analysis for Product: 1H--NMR (CDCl3), δ3.63 (S, 3H, OCH3), 6.7 (d, J=13.5 Hz, 2H), 7.65 (d, J=13.5 Hz, 2H); GCMS (70 ev), M/e (% rel. int.) 228 (M+ +4, 3.3), 226 (M+ +2, 9.2), 224 (M+, 9), 193 (17), 191 (93), 189 (100).