Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[O:16][CH3:17].[Li]CCCC.CN(C)[CH:25]=[O:26]>C1COCC1.O>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH:25]=[O:26]
Reactant: COCOCCc1cc(OC)c(Br)cc1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOCCc1cc(OC)c(C=O)cc1OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
In a round bottom flask, 1-bromo-2,5-dimethoxy-4-(2-methoxymethoxy-ethyl)-benzene (0.55 g, 18.02 mmol) was dissolved in 30 mL of dry THF. The reaction mixture was cooled to −78° C. using a dry ice-acetone bath and stirred for 10 min. A solution of n-BuLi (0.86 mL of 2.5 M solution in hexane) was added and the reaction mixture was stirred for an additional 30 min. Dimethyl formamide (0.26 g, 36.06 mmol) was added and then the temperature was allowed warm up slowly to room temperature and stirred for 30 min. The reaction mixture was diluted with water and the organic material was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated in vacuo. The crude material was purified by flash column chromatography using a hexane and ethyl acetate gradient to give colorless oil in 56% yield. MS (m/z) 255 (M+1)+. 1HNMR(CDCl3): δ ppm 2.96 (m, 2H), 3.32 (m, 3H), 3.75 (m, 2H), 3.79 (s, 3H), 4.13 (s, 3H), 4.63 (s, 2H), 6.98 (s, 1H), 7.26 (s, 1H), 10.40 (s, 1H).
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([Cl:28])[CH2:26][CH3:27].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:27][CH2:26][CH2:25][Cl:28])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep36, 3 g, 8.77 mmol) and K2CO3 (1.2 g, 8.77 mmol) were suspended in dry DMF (45 mL) and stirred at room temperature for 1 h. Then, bromo-chloro-propane (2.7 mL, 17.5 mmol) was added dropwise and the mixture stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated to give the title compound as a pale yellow oil (3.6 g, 98% yield).
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=3)[CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([C:37]([F:40])([F:39])[F:38])[C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[N:9]3[C:5]([S:6][C:7]([C:10]4[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=4)[CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8]3)=[N:4][CH:3]=2)=[CH:31][C:32]=1[C:37]([F:40])([F:38])[F:39]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: CS(=O)(=O)NCc1cccc(-c2nn3c(I)cnc3s2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)NCc1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 105 °C
Yield: 6 %

Procedure:
N-[3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl) -benzyl]-methanesulfonamide (77 mg, 0.177 mmol, 1 eq) was dissolved in 1,4-dioxane (3 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (76 mg, 0.265 mmol, 1.5 eq), K2CO3 (73 mg, 0.531 mmol, 3 eq), H2O (2 mL) and dichlorobis(triphenylphosphine)palladium(II)(12 mg, 0.0177 mmol, 0.1 eq) were added. The reaction mixture was heated in a pressure tube at 105° C. overnight. Solvents were removed and the residue obtained was suspended in water and extracted twice with EtOAc. The organic layers were dried, filtered end evaporated. The residue was triturated with CH3CN and filtered. The solid was purified in an Isolute Si II cartridge (DCM/MeOH, 0%-5%). The product obtained was precipitated in CH3CN and filtered to give the desired product (5 mg, 6%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.70 min, [M+H]+ m/z 469.1; 1H NMR (300 MHz, DMSO) δ 8.88 (s, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 7.90 (m, 1H), 7.80 (s, 1H), 7.73 (t, J=6.3 Hz, 1H), 7.62 (d, J=4.7 Hz, 2H), 6.74 (s, 2H), 4.29 (d, J=6.3 Hz, 2H), 2.93 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:29][CH:28]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:25][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:31][CH:32]=1
Reactant: CC1Cc2ccccc2N1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC1Cc2ccccc2N1Cc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of 2-methylindoline (21 μL, 0.16 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (88 mg, 0.415 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (11-20% acetone/CH2Cl2) to give 3-[4-(2-methyl-2,3-dihydro-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (25 mg, 54%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.98 (br. s., 1H), 7.85 (d, J=8.2 Hz, 2H), 7.56 (s, 1H), 7.48 (d, J=7.8 Hz, 2H), 6.99 (d, J=7.2 Hz, 1H), 6.84-6.94 (m, 1H), 6.53 (t, J=7.4 Hz, 1H), 6.31 (d, J=7.8 Hz, 1H), 4.45 (d, J=16.3 Hz, 1H), 4.14-4.27 (m, 1H), 3.57-3.76 (m, 1H), 3.12 (dd, J=15.8, 8.6 Hz, 1H), 2.56 (dd, J=16.0, 9.4 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]2[O:23][C:10]3[C:11](=[O:22])[N:12]([C@@H:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15](O)=[O:16])[CH2:13][C:9]=3[CH2:8][C:7]=2[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32][CH:31]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:15](=[O:16])[C@@H:14]([N:12]2[CH2:13][C:9]3[CH2:8][C:7]4[C:6]([O:25][CH3:26])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:24]=4[O:23][C:10]=3[C:11]2=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:32][CH:31]=1
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: COC(=O)c1ccc(N)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC3=C(Oc4c(OC)ccc(OC)c4C3)C2=O)nc1
Yield: 15 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (Example 13, step 2c) (200 mg, 0.55 mmol), commercially available 6-aminonicotinic acid methyl ester (116 mg, 0.66 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (116 mg, 0.60 mmol), and N-hydroxybenzotriazole (HOBt) (82 mg, 0.60 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoylamino]-nicotinic acid methyl ester (41 mg, 30.8%), as a white solid. 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 8.88 (br. s., 1H), 8.28 (d, J=6.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.09 (d, J=5.9 Hz, 1H), 4.41 (s, 1H), 4.36 (br. s., 1H), 4.04 (d, J=18.6 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 6H), 3.55 (br. s., 2H), 1.76-1.94 (m, 1H), 1.61-1.74 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: [I-].BrC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: C[n+]1ccccc1Br
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 97 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of benzyl alcohol (216 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 97% yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N(CCCO)c1cccc[n+]1[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(CCCOS(C)(=O)=O)c1cccc[n+]1[O-]
Yield: 63.6 %

Procedure:
Methanesulfonyl chloride (0.17 mL, 2.20 mmole) was added dropwise to a solution of 2-[N-(3-hydroxy-1-propyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide (0.50 g, 1.86 mmole) and pyridine (0.23 mL, 2.84 mmole) in CHCl3 (5 mL, dried over K2CO3) at 0° C. When complete by TLC, the reaction was diluted with CHCl3, washed with ice water, dried (Na2SO4), and concentrated. Silica gel chromatography (10% MeOH/CHCl3) gave the title compound (0.41 g, 64%) as a colorless oil: 1H NMR (250 MHz, CDCl3) δ8.25 (dd, J=6.0, 1.9 Hz, 1 H), 7.25 (m, 4 H), 4.35 (t, J=6.2 Hz, 2 H), 3.75 (t, J=6.6 Hz, 2 H), 3.00 (s, 3 H), 2.00 (m, 2 H), 1.40 (s, 9 H). Unchanged 2-[N-(3-hydroxy-1-propyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide (0.18 g, 36%) could also be recovered from the chromatographic purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[N:8]=[C:7]([NH:17][CH:18]([CH3:20])[CH3:19])[N:6]=1>CO>[CH:14]1([NH:13][C:9]2[N:8]=[C:7]([NH:17][CH:18]([CH3:20])[CH3:19])[N:6]=[C:5]([O:2][CH3:1])[C:10]=2[C:11]#[N:12])[CH2:16][CH2:15]1
Reactant: C[O-]
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(NC2CC2)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(C)C)nc(NC2CC2)c1C#N
Yield: 89.1 %

Procedure:
To a stirred solution of 0.9 gram of sodium methoxide in 100 ml of methanol was added, in one portion, 4.0 grams of 4-chloro-6-cyclopropylamino-2-isopropylamino-5-pyrimidinecarbonitrile. The reaction mixture was then heated under reflux for 3 hours. The methanol was removed by evaporation under reduced pressure to give a residue. The residue was washed with water, and the solid was collected by filtration to yield 3.5 grams of 6-cyclopropylamino-2-isopropylamino-4-methoxy-5-pyrimidinecarbonitrile; mp, 142°-147°.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:12][C:13](=[O:18])[C:14]([CH2:16]O)=[CH2:15])[CH3:11]>ClCCl>[CH2:10]([O:12][C:13](=[O:18])[C:14]([CH2:16][F:7])=[CH2:15])[CH3:11]
Reactant: C=C(CO)C(=O)OCC
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C=C(CF)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of (diethylamino)sulfur trifluoride (DAST) (363 μl, 2.76 mmol) in dichloromethane (1 ml) was slowly added at −78 C a solution of 2-hydroxylmethyl acrylic acid ethyl ester (300 mg, 2.31 mmol) in dichloromethane (3 ml). The reaction mixture was allowed to warm to room temperature, re-chilled to −78 C and additional DAST (100 μl, 0.76 mmol) was added to ensure complete reaction. The reaction mixture was let to warm to room temperature and quenched with saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried (MgSO4). The dichloromethane solution was directly passed through a short silica gel pad, eluted with dichloromethane and the product fractions were collected. The combined fractions (ca. 12 ml) will be directly used in the next step synthesis without further concentration.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[N:22]1(O)C2C=CC=CC=2N=[N:23]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:22]([C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[NH2:23]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.60 g), 1H-1,2,3-benzotriazol-1-ol (0.28 g) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.40 g) at room temperature. The mixture was stirred for 10 min and hydrazine monohydrate (0.28 mL) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.28 g, yield 44%) as colorless crystals. melting point>276° C. (decomposition).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH:3]=[CH:4][C:5](=[O:8])[CH2:6][CH3:7].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH:2]([C@H:3]1[C@@H:12]2[CH2:13][C@H:14]([CH:10]=[CH:11]2)[C@H:4]1[C:5](=[O:8])[CH2:6][CH3:7])([CH3:9])[CH3:1]
Reactant: CCC(=O)C=CC(C)C
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CCC(=O)[C@H]1[C@@H](C(C)C)[C@H]2C=C[C@H]1C2
Temperature: 0 °C
Reaction time: 84 h
Yield: 78 %

Procedure:
Prepared according to general procedure A from 6-methylhept-4-en-3-one (89 μL, 0.60 mmol), cyclopentadiene (99 μL, 1.2 mmol), 70% aqueous perchloric acid (10.3 μL, 0.12 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32 mg, 0.12 mmol) in water (120 μL) for 2.5 days at 0° C. Then, an additional 1.2 mmol of cyclopentadiene was added and the mixture was allowed to stir for an additional 3.5 days at 0° C. Purification by silica gel chromatography (18:1 pentane:ether) provided the title compound as a colorless oil in 78% yield (90 mg, 0.47 mmol); 6:1 endo:exo, endo 90% ee. For the purpose of characterization, the more quickly eluting exo diastereomer was removed by silica gel chromatography as above. IR (film) 3057, 2961, 2869, 1709, 1460, 1367, 1334, 1136, 1028, 904.2, 716.6 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.26 (dd, J=5.7, 3.3 Hz, 1H, CH═CH), 5.79 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 3.14 (m, 1H, CHCH═CH), 2.77 (m, 1H, CHCH═CH), 2.63 (dd, J=3.6, 3.6 Hz, 1H, CHCO), 2.49 (m, 2H, CH2CO), 1.40 (m, 3H, CH(CH3)2 and CHCH2CH), 1.05 (d, J=7.5 Hz, 3H, one of CH(CH3)2), 0.99 (dd, J=4.8, 4.8 Hz, 3H, CH2CH3), 0.84 (d, J=7.5 Hz, 3H, one of CH(CH3)2), 13C NMR (75 MHz, CDCl3) δ 211.6, 139.6, 131.9, 57.8, 49.1, 47.4, 47.2, 45.5, 35.2, 33.1, 22.7, 22.2, 8.5; HRMS (CI) exact mass calc'd for (C13H20O) requires m/z 192.1514, found m/z 192.1513. [α]D=+20.1 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (162° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=4.4 min, and (1S, 2S, 3R, 4S) endo isomer tr=4.2 min, exo isomers tr=3.9, 4.1 min.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.O=[C:15]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:16]([CH:15]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1)[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: NC1COc2ccccc2NC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1COc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
The 3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (0.250 g) is dissolved in 5 ml of methanol and 2.88 g of ethyl 2-oxo-4-phenylbutyrate is added. This is followed by the addition of a solution of 88 mg of sodium cyanoborohydride in 3 ml of methanol and 0.8 ml of glacial acetic acid. The reaction is stirred overnight under nitrogen and concentrated. The residue is dissolved in 20 ml of methylene chloride and washed with 10 ml of cold saturated sodium carbonate. After drying over magnesium sulfate the solution is concentrated to an oil which is purified by flash chromatography on silica gel [solvent, acetone, hexane (1:4)] to afford 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; NMR (CDCl3) δ 9.35 (s (broad, 1], 6.50-7.30 (m, 10, 4.10 (q, 2), 2.67 (t (broad), 2], 1.21 (t, 3); IR (neat) 3220 (NH), 1730 (C=O, ester), 1685 (C=O, lactam) cm-1.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[O:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>CN(C)C=O>[Br:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:13]1[CH2:14][CH2:15][O:11][C:12]1=[O:16]
Reactant: BrCCCCCCBr
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCCCCCBr
Yield: 7.9 %

Procedure:
By the procedure of Example 1, sodium hydride (3.85 g of 50% dispersion in oil, 0.0804 mole), 1,6-dibromohexane (24.5 ml, 0.16 mole) and 2-oxazolidinone (7.0 g, 0.0804 mole) in dimethylformamide (180 ml total) were reacted and the reaction mixture concentrated to one tenth volume. Hexane (200 ml) was added, salts were removed by filtration, and the heavy, oily layer separated from the filtrate. This heavy layer was chromatographed on silica gel with ethyl acetate as eluant and tlc monitoring. Clean product-containing fractions were combined and evaporated to yield the title product as an oil [1.59 g; Rf 0.5 (ethyl acetate)].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30](O)=O)[CH:15]=1>>[F:34][C:13]([F:12])([F:33])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[CH:15]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)cn1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.128 g, 0.60 mmol) and 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example D.12) (0.135 g, 0.403 mmol) according to the general procedure V. Obtained as a light yellow solid (0.022 g, 12%). MS (ISP) 452.1 [(M+H)+]; mp 229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[C:14]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH2:15][C:16]([O-])=[O:17].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[C:21]([O:20][C:14](=[O:19])[CH2:15][C:16]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]([F:11])([F:12])[F:13])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: FC(F)(F)CNc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)N(CC(F)(F)F)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
(4-Chlorophenyl) (2,2,2-trifluoroethyl)amine (1.84 g, 8.8 mmol) and mono-t-butyl malonate (1.37 mL, 8.9 mmol) were dissolved in DCM (50 mL) and the solution cooled in an ice bath prior to portion wise addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.71 g, 8.9 mmol). After one hour the reaction was complete by TLC and was diluted with ethyl acetate and sequentially washed with 1 N NaOH, 1N HCl, and brine. The organic layer was dried with MgSO4 and concentrated under reduced pressure to give a white solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (9H, s), 3.13 (2H, s), 4.34 (2H, q, J=8.7 Hz), 7.22 (2H, m), 7.41 (2H, m).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:39][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([CH2:31][N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:37][CH:36]=4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: CN1CCN(Cc2ccc(CN)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(NCc4ccc(CN5CCN(C)CC5)cc4)sc3c2)ccn1
Temperature: 80 °C

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (25 mg, 0.072 mmol, 1.0 eq) in 2 mL of NMP was added (4-((4-methylpiperazin-1-yl)methyl)phenyl)methanamine (23 mg, 0.108 mmol, 1.5 eq) and DIPEA (37 μL, 0.216 mmol, 3.0 eq) and reaction mixture heated at 80° C. in oil bath for 12 hours. Thereafter, the product was purified via reverse phase HPLC. LC/MS (m/z) [503.1] (MH+).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH2:10].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:11]1(/[CH:9]=[CH:10]/[C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CC1CCCCC1
Reactant: O=Cc1ccc(Br)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccc(/C=C/C2CCCCC2)o1
Temperature: 25 °C

Procedure:
A mixture of 5-bromofuran-2-carbaldehyde (1.03 g, 5.89 mmol), vinylcyclohexane (0.86 g, 7.80 mmol), P(o-Tol)3 (0.089 g, 0.29 mmol), Pd(OAc)2 (0.070 g, 0.31 mmol) and Et3N (2.0 mL) in anhydrous DMF (3.0 mL) was degassed by bubbling Ar then alternating vacuum/Ar three times. The reaction mixture was heated under inert atmosphere at +90° C. for 20 hrs and cooled to room temperature. Aqueous NH4Cl was added to the reaction mixture and the mixture was extracted twice with hexanes and EtOAc. Combined organic layers were washed with brine, concentrated under reduced pressure. Purification by flash chromatography (3%-8% EtOAc—hexanes gradient) gave (E)-5-(2-cyclohexylvinyl)furan-2-carbaldehyde as a yellow oil. Yield (0.40 g, 33%); 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.19 (d, J=3.8 Hz, 1H), 6.55 (dd, J=7.0, 16.1 Hz, 1H), 6.34 (d, J=3.5 Hz, 1H), 6.19-6.26 (m, 1H), 2.10-2.19 (m, 1H), 1.52-1.92 (m, 6H), 1.10-1.42 (m, 4H).