Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:11]2[CH:10]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C:24]([O:26]C)=[O:25])[CH:18]=[CH:17]4)=[O:13])[CH:8]=[CH:7][C:6]=2[C:5]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:4][CH2:3]1.O.O.[OH-].[Li+].Cl>O1CCCC1.CO>[CH3:1][C:2]1([CH3:35])[C:11]2[CH:10]=[C:9]([CH:12]([OH:13])[C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]4)[CH:8]=[CH:7][C:6]=2[C:5]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc2cc(C(=O)c3ccc4c(c3)C(C)(C)CC=C4c3ccc(C)cc3)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(O)c4ccc5cc(C(=O)O)ccc5c4)ccc32)cc1

Procedure:
0.5 g (1.08 mmol) of methyl 6-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylcarbonyl)-2-naphthalenecarboxylate is dissolved in 15 ml of tetrahydrofuran, 15 ml of water and 5 ml of methanol, and 0.14 g (3.25 mmol) of lithium hydroxide monohydrate is then added. The medium is refluxed for 2 hours, treated with 1N hydrochloric acid solution and extracted with ethyl acetate. The residue obtained is recrystallized from an ethyl acetate/heptane mixture. A white solid is obtained (0.45 g; yield=94%; 110° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[C:13](=O)[NH:14][N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:13]1[N:14]=[N:15][CH:16]=[C:11]2[CH:10]=[C:9]([CH3:18])[N:8]([CH2:7][C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:12]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2c(C)cc3cn[nH]c(=O)c32)cc1
Product: COc1ccc(Cn2c(C)cc3cnnc(Cl)c32)cc1
Yield: 76 %

Procedure:
17.8 g (66 mmol) of 1-(4-methoxybenzyl)-2-methyl-6,7-dihydropyrrolo[2,3-d]pyridazine-7-one are reacted at 100° C. for 2 h in 130 ml of phosphorus oxychloride. Purification: chromatography on silica gel (eluent: ethyl acetate). Yield: 76%. M.p.: 126°-128° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)(=[O:23])=[O:22]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 2-aminothiazole (15.08 g, 0.1506 mol) in methylene chloride (100 mL) and pyridine (24 mL, 0.30 mol) was added dropwise over 20 minutes a solution of 2,4-difluorobenzenesulfonyl chloride (10 mL, 0.07 mol) in 10 mL of methylene chloride. After stirring at room temperature for 48 hours the reaction was concentrated and purified by flash column chromatography eluting with hexane/ethyl acetate. LCMS Rt=1.21 minutes MS m/z 277 [MH]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].[C:13]([N:17]=[C:18]=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:12][C:18](=[O:19])[NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[S:11]
Reactant: Cc1cccc(C)c1NC(N)=S
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1NC(=S)NC(=O)NC(C)(C)C

Procedure:
To a mixture of 8.8 g. (0.05 mole) of 1-(2,6-dimethylphenyl)thiourea and 10 ml. of xylene is added 5 g. of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dimethylphenyl)-3-(t-butylcarbamyl)thiourea.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:35])[C@@H:6]1[CH2:13][N:12]2[C:14]3[CH:15]=[C:16]([C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:18][C:19]=3[C:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:11]2[C:10]2[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=2[O:8][CH2:7]1.[CH:36](OCC(F)(F)F)=O>C1COCC1>[CH:21]1([C:20]2[C:19]3[CH:18]=[CH:17][C:16]([C:27]([O:29][CH3:30])=[O:28])=[CH:15][C:14]=3[N:12]3[C:11]=2[C:10]2[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=2[O:8][CH2:7][C@H:6]([N:5]([CH3:35])[CH2:4][CH2:3][CH2:2][NH:1][CH3:36])[CH2:13]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=COCC(F)(F)F
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCCN)COc1ccccc1-3
Solvent: C1CCOC1
Product: CNCCCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl(7R)-7-[(3-aminopropyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.16 M) in THF was treated dropwise with 2,2,2-trifluoroethyl formate (1.3 eq.) and stirred overnight at RT. The volatiles were removed in vacuo and the residue dissolved (0.08 M) in THF and treated dropwise with BH3-DMS complex (2 M in THF; 10 eq.). The resulting solution was stirred at RT for 3 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution refluxed for 2 h. The volatiles were then removed in vacuo and the residue partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (EtOAc/MeOH/Et3N 90:8:2) affording the product as a pale orange solid (80% overall for steps 2, 3, 4, 5). (ES) m/z 490 (M+H)+.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[C:25]#[N:26])=[CH:19][CH:18]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[C:25]#[N:26])=[CH:19][CH:18]=3)[N:14]=2)[NH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)c4nccs4)cc3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)c4nccs4)cc3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
To a 25 ml one necked round bottom flask, 3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(thiazol-2-yl)acrylonitrile (0.09 g, 0.000161 mol) was taken in CH2Cl2 (10 ml) followed by dropwise addition of TFA (2.0 ml) at 0°-5° C. and the reaction was allowed to stir at room temperature for 24 hr. After completion of the reaction, the pH of the solution was adjusted to neutral by the addition of saturated sodium bicarbonate solution and the product was extracted with CH2Cl2. The combined organic layer was dried over anhy. sodium sulphate and concentrated to obtain crude mixture which was dissolved in ethanol (10 ml) and NaOAc.3H2O (0.219 g, 0.00161 moles) was added and the reaction mixture was stirred it at room temperature for 20 hr. Ethanol was removed and the reaction mixture was diluted with water, followed by extraction with ethyl acetate. The combined organic layers were dried over sodium sulphate, concentrated to afford crude product which was purified using column purification by eluting the compound with 50% ethyl acetate in hexanes to yield 35.0 mg of 3-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(thiazol-2-yl)acrylonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCCCCCCl
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCOc1cccc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 15.0 g (0.088 mole) of 3-hydroxybiphenyl, 13.3 g (0.097 mole) of 6-chlorohexan-1-ol, and 13.8 g (0.01 mole) of potassium carbonate in 250 ml of dry dimethylformamide is stirred and heated to reflux for 3 hours. The mixture is cooled to room temperature, diluted with water, and extracted with ether, the ether extracts dried and evaported under reduced pressure to give a light yellow oil. The crude product is vacuum distilled to give a fraction boiling between 150 and 190° C. (0.05 mmHg), and solidifying to a soft solid, corresponding to the pure desired product.
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[C:7](#[N:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:1][C:2]([CH3:6])=[C:3]([CH3:4])[C:8]=1[C:7]#[N:11]
Reactant: CC(=O)C(C)S
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1sc(N)c(C#N)c1C
Temperature: -2 °C
Yield: 64.2 %

Procedure:
A solution of 3-mercapto-2-butanone (1.00 kg, 9.0 mole, 93.6% assay) in 2.0 L SDA 3C 200 Proof, absolute Ethanol (Ethanol) is prepared in a 5 L 1N RBF fitted with torian and transfer tubing. Malononitrile (588.8 g, 8.9 mole) is dissolved in 5.0 L Ethanol and cooled to 4° C. at which point triethylamine (250 mL, 1.8 mole, 0.2 eq) is added with a 560 mL ethanol rinse. The anionic malononitrile solution is cooled to −2° C. and the 3-mercaptobutanone solution is added over 1.3 hrs at −1 to −5° C. After an hour, the reaction shows less than 0.1% malononitrile. The reaction is concentrated on the rotovap (40° C. bath) to a slurry of approximately 2.5 L and 3.0 L of heptanes are added. The slurry is cooled to 5° C. for 30 minutes and the solids collected by filtration. The solids are rinsed with 2.5 L of 20% Ethanol in heptanes in 7 portions. The excess solvent is removed on the filter, and the wet cake dried in a vacuum oven overnight at 40° C. and full vacuum to give an off white solid as 2-amino-4,5-dimethylthiophene-3-carbonitrile (870 g, 64.1% yield, 99.7% purity shown by HPLC). The filtrates are reconcentrated to an oily slurry which is filtered and rinsed with 0.5 L of 20% Ethanol in heptanes. The second crop of solids is dried separately (47 g, 3.5% yield, 98.6% purity shown by HPLC). 1H NMR (400 MHz, DMSO-d6) δ 1.93 (d, J=1.2 Hz, 3H), 2.07 (d, J=1.2 Hz, 3H), 3.33 (s, 2H). MS 153 (MH+). HPLC Retention Time: approximately 10.9 minute (Phenomenex Luna C18 (2) column, acetonitrile/water with 0.1% AcOH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH2:1][Br:17])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 3,5-dimethylbromobenzene (80.25 g, 0.43M), NBS (77 g, 0.43 M), and benzoyl peroxide (5.2 g, 0.021 M) in carbon tetrachloride (400 mL) was refluxed for 3 hr. under a light of 500 W tungsten light. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a white solid, which was purified by silica gel column chromatography (eluent: hexane) to afford 82 g (72%) of a white solid. m.p. 46-47° C.; 1H NMR (200 MHz, CDCl3) δ 2.32 (3H, s), 4.38 (2H, s), 7.12 (1H, s), 7.25 (1H, s), 7.33 (1H, s).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([OH:18])(=O)[C@H:14]([CH3:16])[OH:15].ON1C2C=CC=CC=2N=N1.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34][NH2:35]>CN(C)C=O.ClCCl>[F:29][C:30]([F:43])([F:44])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=1)[CH2:34][NH:35][C:13](=[O:18])[C@H:14]([CH3:16])[OH:15]
Reactant: C[C@H](O)C(=O)O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 g) was added to a solution of L-(+)-lactic acid (1.17 g) and 1-hydroxybenzotriazole (1.99 g) in dimethyl formamide (15 ml) at 0° C. under a nitrogen atmosphere. After stirring for 30 mins, 3,5-bistrifluoromethylbenzylamine was added and the solution was stirred at room temperature for 16h. The solution was diluted with dichloromethane (150 ml) and washed with sodium bicarbonate solution, water and brine. After drying (Na2SO4) the solvent was evaporated in vacuo to leave a viscous yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:30][CH2:29][CH:28]([C:25]3[S:26][CH:27]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=3)[CH2:33][CH2:32]2)=[O:16])[O:4][N:3]=1
Reactant: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCC(c3nc(-c4ccccc4)cs3)CC2)c1C

Procedure:
A solution of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (200 mg, 1.02 mmol), 4-(4-phenyl-1,3-thiazol-2-yl)piperidine (250 mg, 1.02 mmol) and diisopropylethylamine (0.357 ml, 2.05 mmol) in dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (201 mg, 51.5%) as a solid. mp 156-157° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14].[OH-].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>CS(C)=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1c(C)nc2ccccc2c1N
Reactant: Fc1ccccc1CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone in dimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized 85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixture was stirred at ambient temperature for twenty minutes, and thereafter a solution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml) was added dropwise. The mixture was stirred for two hours and allowed to stand overnight at room temperature. Thereafter, it was poured onto ice and diluted with water to form a tacky lump. This was allowed to stand for fifteen minutes, and the aqueous dimethylsulfoxide was decanted. The tacky precipitate was dissolved in dichloromethane, washed with water (3x) and saturated sodium chloride solution, and dried over sodium sulfate. Removal of the sodium sulfate by filtration and the solvent by evaporation gave 26.5 g of viscous oil.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:33])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:33])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 170 mg (0.58 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 124 mg (0.70 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.31 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 295 mg of resultant crude imine are cyclized in the same way as in Example 1 at −20° C. using 2.6 ml (2.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 25 mg of product.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([O:22][C:23]([NH:25][NH2:26])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(O)(=O)C>[CH2:15]([O:22][C:23]([NH:25][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NNC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 57 %

Procedure:
To a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g), benzylhydrazinecarboxylate (16.7 g), DCM (150 mL), and acetic acid (5.75 mL) was added sodium triacetoxyborohydride (31.9 g), followed by stirring at room temperature for 2.5 days. To the reaction liquid was added water, and the organic phase was separated. The aqueous phase was extracted with chloroform, and the combined organic phase was washed with water, a saturated aqueous sodium bicarbonate, and saturated brine in this order, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain tert-butyl 4-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (10.0 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(-c4ccncc4)nc3s2)cc1
Yield: 26 %

Procedure:
The titled compound (yield=26%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except that 1D (Example 1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 7.68 (d, J=8.34 Hz, 2H) 8.12 (d, J=8.34 Hz, 2H) 8.29-8.46 (m, 4H) 8.87 (br. s., 2H) 13.15 (br. s., 1H); ESI-MS: m/z 391.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:12][PH:13](=[O:15])[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:8][C:9]([CH:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:12][P:13]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:14])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 48.5 %

Procedure:
To a solution of 2,4-di-(benzyloxycarbonyl)butylphosphinic acid (6) (19.3 g, 49.4 mmol) in tetrahydrofuran was added benzyl alcohol (5.3 g, 49.3 mmol) and dimethylamino in tetrahydrofuran was added benzyl alcohol (5.3 g, 49.3 mmol) and dimethylamino pyridine (0.5 g). Dicylcohexylcarbodiimide (DCC, 12 g, 58 mmol) was added and a white precipitate formed. After 30 minutes the white suspension was filtered and the filtrate evaporated under reduced pressure. The clear and colorless oil was purified by flash chromatography and eluted with 1:1 Hex./EtOAc to give 2,4-di(benzyloxycarbonyl)butylbenzylphosphinic acid (7) (11.5 g, 47%) as a clear and colorless oil. Rf. 0.16 (1:1 Hex./EtOAc); 1H NMR (CD1C3): 7.3 ppm (m, 15H), 7.2 ppm (d, 1H), 5.0 ppm (m, 6H), 2.9 ppm (m, 1H), 2.2 ppm (m, 3H), 1.9 ppm (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28].O>CN(C=O)C>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Next, to a mixture of tert-butyl (7-hydroxy-1-naphthyl)carbamate (64.0 g, 247 mmol) and cesium carbonate (161 g, 493 mmol) in 300 mL anhydrous DMF was added iodoethane (42.3 g, 272 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hours. Water was added to the mixture, and the product was extracted with ethylacetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitate was collected and dried to afford tert-butyl (7-ethoxy-1-naphthyl)carbamate (47.9 g, 67.5% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C@H:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=O.C1C=CC2N(O)N=[N:23]C=2C=1.O.CN1CCOCC1.[O:35]=[C:36]1[CH2:53][CH2:52][C:51]2=[CH:54][N:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:50]=32)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][NH:37]1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:12]([O:11][C:9](=[O:10])[CH2:8][C@H:4]([C:5](=[O:7])[NH:23][C@H:53]1[CH2:52][C:51]2=[CH:54][N:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:50]=32)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:36]1=[O:35])[CH2:3][CH:2]([CH3:1])[CH3:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: O=C1CCc2cn(c3ccccc23)CCCCCCN1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 62.7 %

Procedure:
Alternatively, to a solution of (2R)-4-methyl-2-(t-butoxycarbonylmethyl)pentanoic acid as prepared above (2.39 g, 10.4 mmol), HOBt-H2O (2.5 g, 1 eq.), N-methylmorpholine (2.3 mL, 2 eq.), and (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19), 13(18),14,16-tetraene (2.96 g, 1 eq.) in dry DMF (200 mL) under argon was added EDCI (3.96 g, 2.0 eq.). The resulting mixture was stirred overnight, then the next morning the DMF was removed at 35° C. under high vacuum. The residue was partitioned between CH2Cl2 (150 mL)/water (75 mL), then the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL). After drying the CH2Cl2 layer over Na2SO4, it was filtered and evaporated to dryness. Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether) gave (3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (3.24 g, 62.7%).