Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]#[CH:4]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)CCCC(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: C=CC(C)(O)CCCC(C)C

Procedure:
An autoclave having an internal volume of 3 liters was charged with 1,140 g of the hexane solution containing 3,7-dimethyl-1-octyn-3-ol thus obtained and 0.27 g of a Lindlar catalyst (supported on calcium carbonate) to carry out the hydrogenation for 4 hours under hydrogen pressure of 5 to 8 kg/cm2 (gauge pressure) at a temperature of 25 to 43° C. Thereafter, the catalyst was filtered off, and the resultant filtrate was concentrated with a rotary evaporator to give crude 3,7-dimethyl-1-octen-3-ol. Above the procedures for the hydrogenation of 3,7-dimethyl-1-octyn-3-ol were repeated once more to obtain, in total, 1,590 g of crude 3,7-dimethyl-1-octen-3-ol. Analysis by gas chromatography (column: DC-550, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 100° C.; and column: PEG-HT, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 130° C.) revealed that the conversions of 3,7-dimethyl-1-octyn-3-ol were 99.7% and 97.3% for the respective runsof the hydrogenation, and the selectivities to 3,7-dimethyl-1-octen-3-ol were 95.0% and 95.8%, respectively.
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]=O.C([BH3-])#N.[Na+]>>[CH3:21][C@@H:20]1[N:22]([C:23]2[N:28]=[C:27]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[CH:30]3)[CH:26]=[CH:25][N:24]=2)[CH:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)[N:17]2[C@H:16]1[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH2:19][CH2:18]2
Reactant: O=Cc1ccccn1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H]1[C@@H]2CN(C(=O)Nc3cccc4ccccc34)CCN2C(c2ccccn2)N1c1nccc(-n2cnc3ccccc32)n1

Procedure:
The title compound was prepared from 2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 18.8 mg), 2-pyridinecarboxaldehyde (24.5 mg), and sodium cyanoborohydride (4.8 mg) according to the procedure described in Example 14, Step G. Mass spectrum (ESI) 582.2 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1.[NH:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:14]([C:16](O)=[O:17])[CH3:15].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:1]1([NH:4][C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:16](=[O:17])[C@@H:14]([NH:13][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:15])[CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(F)c1NC1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(F)c1NC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N1-cyclopropyl-6-fluorobenzene-1,2-diamine (392.7 mg, 2.363 mmol) in DMF (3 mL) was added Boc-L-Ala-OH (447 mg, 2.363 mmol), 1,1′-dimethyltriethylamine (822 μL, 4.73 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (1.23 mg, 2.36 mmol) and the resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using EtOAc:DCM (1:1) as eluent to give (S)-tert-butyl 1-(2-(cyclopropylamino)-3-fluorophenylamino)-1-oxopropan-2-ylcarbamate: LC-MS (ESI) m/z 338.2 [M+H]+.
Reaction SMILES: C([NH:20][CH:21]1[C:42](=[O:43])[N:23]2[CH:24]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:25]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[S:26][C@H:22]12)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1>CC(C)=O>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[NH2:20][CH:21]1[C:42](=[O:43])[N:23]2[CH:24]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[C:25]3([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[S:26][C@H:22]12
Reactant: O=C(OCc1ccccc1)C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC12CCCCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCCCC3)S[C@H]12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36.5 %

Procedure:
To a magnetically stirred solution of 31.4 g. (0.0534 mole) of benzyl 6'-tritylamino-spiro[cyclohexane-1,2'-penam]-3'-carboxylate in 300 ml. of anhydrous acetone, there is added a solution of 10.2 g. (0.0535 mole) of p-toluene-sulfonic acid monohydrate in 300 ml. of anhydrous acetone. After stirring for 2.5 hours at ambient temperature, a precipitate is obtained which is removed by filtration, washed with acetone and then with diethyl ether and dried. 10.1 g. of benzyl 6'-amino-spiro[cyclohexane-1,2'-penam]-3'-carboxylate p-toluenesulfonate are obtained. Yield: 36.5%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:22]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 11 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (5-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC:
Reaction SMILES: CCC(N)CC.O[CH2:8][CH2:9][NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13].O=S(Cl)[Cl:18]>>[Cl-:18].[Cl:18][CH2:8][CH2:9][NH2+:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13]
Reactant: CCC(CC)NCCO
Reactant: O=S(Cl)Cl
Agent: CCC(N)CC
Product: CCC(CC)[NH2+]CCCl
Product: [Cl-]

Procedure:
3-Pentylamine was converted to N-(2-hydroxyethyl)-N-(3-pentyl)amine according to Method B5a. The amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(3-pentyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(3-pentyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:22]=[CH:23][C:24](O)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:23]=[CH:22][C:21]([Br:20])=[CH:26][N:25]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Oc1ccc(Br)cn1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.12 g) synthesized in Example 4 and 5-bromopyridin-2-ol (1.22 g) were dissolved in tetrahydrofuran (20 mL), triphenylphosphine (2.02 g) and diisopropyl diazodicarboxylate (40% toluene solution, 4.14 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and hexane (about 10 mL) was added. The precipitated crystals were removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (1.84 g) as a pale-yellow oil.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17]CC)=[O:16])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C.O1CCOCC1>[C:3]([NH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([OH:17])=[O:16])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cccc(NC(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
4N Aqueous solution of sodium hydroxide (2 ml) was added to a solution of ethyl 3-(benzoylamino)benzoate (695 mg) in ethanol (5 ml) and 1,4-dioxane (5 ml). After stirred at 50° C. for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated to give 3-(benzoylamino)benzoic acid (595 mg) as solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH2:6]>>[CH:8]1([O:7][CH:5]=[CH:6][C:1]([Cl:4])=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=COC1CCCCC1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)C=COC1CCCCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
50 g (0.5 mol) of phosgene were condensed into a stirred apparatus fitted with a -78° C. dry-ice condenser. 50.5 g (0.4 mol) of cyclohexyl vinyl ether were subsequently added dropwise at 20° C. over the course of 3 hours. The mixture was subsequently stirred at 50° C. for a further 5 hours. The excess phosgene was expelled by means of nitrogen, and the crude product was worked up by distillation at 110° C./2.5 mbar, giving 66.4 g (88%) of valuable product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:39]2[S:43][C:42]([C:44]3([OH:48])[CH2:47][CH2:46][CH2:45]3)=[N:41][CH:40]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[N:8]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:39]2[S:43][C:42]([C:44]3([OH:48])[CH2:45][CH2:46][CH2:47]3)=[N:41][CH:40]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[N:8]([S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=3)(=[O:31])=[O:30])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C4CCNCC4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-(5-chloro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 50A) (120 mg, 0.169 mmol) in dichloromethane (846 μl) was added trifluoroacetic acid (652 μl, 8.46 mmol). The reaction was stirred for 1 hour and was then concentrated to dryness. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous bicarbonate solution (1 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 609.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1)[CH3:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:45][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C)C=O>[C:28]([O:27][C:26]([NH:25][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C:23]([OH:45])=[O:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.9 %

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(1-ethyl-4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (180 mg, 0.39 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was added PDC (716 mg, 1.90 mmol, 4.88 equiv) and the resulting solution was stirred for 14 hrs at 25° C. The reaction was then quenched by the addition of 20 mL of water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give the desired 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl]amino]-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]acetic acid (100 mg, 54%) as a colorless oil. MS (ES): m/z 476 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:32])=[C:21]([NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1>>[ClH:1].[C:24]([NH:23][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][C:20]=1[F:32])[NH:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Product: COc1cc2nccc(Nc3ccc(F)c(NC(=O)c4ccccc4)c3)c2cc1OC
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6,7-dimethoxyquinoline was reacted with N-(5-amino-2-fluorophenyl)benzamide to give the title compound; NMR: 3.98 (s, 3H), 4.0 (s, 3H), 6.73 (d, 1H), 7.34 (m, 1H), 7.43 (s, 1H), 7.46 (d, 1H), 7.55 (m, 4H), 7.82 (dd, 1H), 7.98 (d, 2H), 8.13 (s, 1H), 8.37 (d, 1H), 10.32 (broad s, 1H), 10.67 (broad s, 1H); Mass: M+H+ 418.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].[CH2:14]([OH:16])[CH3:15]>>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:16][CH2:14][CH3:15])=[O:11]
Reactant: CCO
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)Cl
Product: CCOC(=O)[C@@H]1[C@@H](C=C2CCC2)C1(C)C

Procedure:
A solution of 12 g of (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride and 25 ml of ethanol was stirred at room temperature for 8 hours and was evaporated to dryness at 45° C. under reduced pressure. The residue was taken up in isopropyl ether and the solution was washed with water, dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with a 9-1 petroleum ether (b.p.=60°-80° C.)--isopropyl ether mixture. The fraction with an Rf=0.35 was evaporated to dryness under reduced pressure at 45° C. and the product was rectified to obtain 8 g of ethyl (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 78°-79° C. at 0.1 mm Hg and a specific rotation of [α]D20 =-18° (c=2% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(Cl)n1
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
143.6 g (one mole) of 2-chloro-6-methoxy-pyridine were added dropwise with stirring over one hour to a mixture of 1600 ml of concentrated sulfuric acid and 800 ml of fuming nitric acid cooled to 0° C. and the temperature was allowed to rise to 20° C. over three hours. The mixture was then stirred at 20° C. for three hours and was poured into 5000 g of crushed ice. The mixture was vacuum filtered and the product was washed with a large volume of water until acid free and dried to obtain 151-156 g (80-83% yield) of 2-chloro-3nitro-6-methoxy-pyridine in the form of yellow crystals melting at 67° to 69° C. with a purity of 84 to 85%.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:13]=[CH:12][C:11]=2[OH:20])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:21]=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(O)CCC>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:13]=[C:12]([CH2:21][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[C:11]=2[OH:20])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCNCC
Reactant: C=O
Reactant: OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: CCCCO
Product: CCN(CC)Cc1cc(CCCO)cc(-n2nc3ccccc3n2)c1O
Temperature: 105 °C
Yield: 97 %

Procedure:
In 25 ml of n-butanol were dissolved 26.9 g (0.1 mols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)phenol synthesized in Example 8, 5.2 g of 80% paraformaldehyde and 11.0 g (0.15 mols) of diethylamine. The solution was refluxed with heating at 105° C. for 24 hours. After completion of the reaction, the solvent and remaining raw materials were collected under reduced pressure, giving 35.9 g of objective 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)-6-(N,N-diethylaminomethyl)phenol as a brown oil (yield 97.0%, purity 95.6%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH:34]([CH3:36])[CH3:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-phenyl-propan-1-one (0.500 g, 1.15 mmol, Example 52) and acetone (0.084 mL, 1.15 mmol) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.365 g, 1.72 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (1% MeOH in EtOAc) affording 460 mg (83%) of the pure titled compound as a white foam: mp 45-58° C. APCI-MS m/z 478.4 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:49]=[CH:48][C:11]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:47]=[CH:46][C:27]([C:28]([NH:30][C:31]5[CH:32]=[C:33]6[C:37](=[CH:38][CH:39]=5)[N:36]([CH2:40][C:41](OCC)=[O:42])[CH:35]=[CH:34]6)=[O:29])=[CH:26][CH:25]=3)[CH:19]=[CH:18]4)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:47]=[CH:46][C:27]([C:28]([NH:30][C:31]5[CH:32]=[C:33]6[C:37](=[CH:38][CH:39]=5)[N:36]([CH2:40][C:41]([NH:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:42])[CH:35]=[CH:34]6)=[O:29])=[CH:26][CH:25]=3)[CH:19]=[CH:18]4)=[O:13])=[CH:48][CH:49]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21
Reactant: COC(=O)CN
Product: COC(=O)CNC(=O)Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21

Procedure:
Compound 971 was prepared by treatment of Compound 962 with methyl aminoacetate. [M+H]+ calcd for C40H38N6O6: 699.29; found 699.25.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1)C1C=CC=CC=1.CO>C1COCC1.[Pd]>[CH3:25][N:22]1[C:23]([CH3:24])=[C:19]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[CH2:17][CH2:18][C@H:9]([NH2:8])[CH2:10]3)[C:20]([CH3:26])=[N:21]1
Reactant: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](NCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N)C2
Reaction time: 21 h
Yield: 83.8 %

Procedure:
A solution of (2S)-benzyl-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amine (0.287 g, 0.832 mmol) in THF (4 mL) was added to Pd/C (0.10 g, 10% weight of Pd on activated carbon), and MeOH (10 mL) was added to the suspension. The reaction mixture was stirred under H2 (g) atmosphere (balloon) for 21 h. It was filtered through Celite washing with AcOEt (2×10 mL), the solvent was concentrated off and the crude was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH 95:5:1), to yield 0.178 g of the title product (Rf=0.2 (AcOEt/MeOH/Et3N 20:3:2), pale yellow colored oil, 84% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)=[N:10]1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)[NH:12][C:13]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 42.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-cyano-1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.32 g, 0.63 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.13 g, 0.75 mmol) according to the procedure as described in Example 3 to give the title compound as a pale yellow solid (0.15 g, 42%). The compound was characterized by the following spectroscopic data: