Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:26]([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:25]=[CH:24][C:7]=3[C:8](=[O:23])[N:9](CC3C=CC(OC)=CC=3OC)[C:10]=2[CH:11]=1.[CH3:33][O:34][C:35]1[N:40]=[C:39]([CH3:41])[C:38](B(O)O)=[C:37]([CH3:45])[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:34][C:35]1[N:40]=[C:39]([CH3:41])[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:26]([CH:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[N:25]=[CH:24][C:7]=4[C:8](=[O:23])[NH:9][C:10]=3[CH:11]=2)=[C:37]([CH3:45])[CH:36]=1
Reactant: COc1cc(C)c(B(O)O)c(C)n1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(Br)cc32)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn(C4CCOCC4)c23)c(C)n1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
7-bromo-5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one obtained in Preparation Example 1(4) (41 mg) was dissolved in DMF (2 mL). (6-methoxy-2,4-dimethylpyridin-3-yl)boronic acid obtained in Preparation Example 24 (15 mg), Pd(PPh3)4 (4.8 mg), cesium carbonate (54 mg) and water (0.5 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 150° C. for two hours. The reaction mixture was returned to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a 5 N aqueous sodium hydroxide solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (3.7 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:57]([NH:59][CH2:60][C:61](O)=[O:62])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:44]([NH:54][C@H:55]([C:57]([NH:59][CH2:60][C:61]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:62])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-alanyl-glycine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[C:9]([OH:11])=[O:10]>N1C=CC=CC=1>[CH3:5][O:6][N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:1](=[O:3])[CH3:2])[CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: CC(=O)Cl
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Solvent: c1ccncc1
Product: CON=C(C(=O)O)c1cccc(OC(C)=O)c1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
Acetyl chloride (4.1 g.) was added with stirring and ice-cooling to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (5 g.) in pyridine (20 ml.) and the mixture was stirred for 50 minutes at ambient temperature. The reaction mixture was poured into ice-water, adjusted to pH 2.1 and extracted three times with ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was thoroughly removed under reduced pressure to give 2-methoxyimino-2-(3-acetoxyphenyl)acetic acid (syn isomer) (6.1 g.).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[N:22]1([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:34][C:31]3[CH:30]=[CH:29][C:28]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:33][N:32]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccc(N2CCOCC2)cn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cn3)ncc12
Temperature: 25 °C
Yield: 26.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL). The solid obtained was refluxed in ethyl acetate (15 mL), cooled and filtered to give 6-bromo-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a dark brown-gray solid (0.350 g, 26.7%). 1H NMR δ(400 MHz, CDCl3) 8.78 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.97 (s, 1H), 7.32 (dd, J=2.9, 9.0 Hz, 1H), 5.99 (m, 1H), 3.89 (m, 4H), 3.16 (m, 4H), 2.61 (s, 3H), 2.30 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][C:10]1[C:11](=[O:28])[C:12]2[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=2[C:14]2[C:23]=1[S:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2>O.C(OCC)(=O)C>[OH:28][C:11]1[C:10]([CH3:9])=[C:23]2[C:14]([NH:15][C:16]3[C:21]([S:22]2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]2[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=12
Reactant: Cc1c2sc3ccccc3nc-2c2ccccc2c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c2c(c3ccccc3c1O)Nc1ccccc1S2
Reaction time: 2 h

Procedure:
A solution of sodium hydrosulfite (40 g) in water (0.5 l) was added to a suspension of 6-methyl-5H-benzo[a]phenothiazine-5-one (10.4 g) in ethyl acetate (1 l) and stirred for 2 hours. The organic layer was decanted, dried and evaporated to dryness. The resulting residue was triturated with ether and filtered to afford 5-hydroxy-6-methyl-12H-benzo[a]phenothiazine as an air sensitive solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH2:15][CH:14]=[CH2:13])([OH:12])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
3-Oxo-azetidine-1-carboxylic acid tert-butyl ester (1.37 g, 8 mmol) was dissolved in Et2O (10 ml) and a 1M solution of allylmagnesiumbromid in Et2O (10.4 ml, 10.4 mmol) was added dropwise at 0° C. Stirring was continued at rt overnight. The reaction mixture was quenched with H2O, extracted twice with EtOAc, the organic layer were washed with brine, combined, dried over Na2 SO4, filtered off and concentrated under reduced pressure to give a orange oil. The crude product was purified by flash chromatography (silica gel, EtOAc/cyclohexane 15-25%) which furnished the product as an yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Reactant: COCCN
Product: COCCNCC(=O)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Yield: 94.1 %

Procedure:
Prepared from 2-chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (Example 38 step A) (150 mg, 0.406 mmol, HPLC 1.185 min) and 2-methoxyethylamine (700 ul, 8.1 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white solid (156 mg, 94%, HPLC 0.576 min), MS (ISP) m/e=409.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([O:8][CH3:9])[CH:7]=1.ClC(Cl)(Cl)C(=N)O[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: N=C(OCN1C(=O)c2ccccc2C1=O)C(Cl)(Cl)Cl
Reactant: COc1cc(Cl)ccc1C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)c(CN2C(=O)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a solution of 5-chloro-2-methylanisole (200 mg, 1.28 mmol, purchased from APOLLO) and (1,3-dioxoisoindolin-2-yl)methyl 2,2,2-trichloroacetimidate (411 mg, 1.28 mmol, Synthesis, 2003, 7, 1065-1070) in DCM (30 mL) was added trimethylsilyl trifluoromethansulfonate (14.2 mg, 0.064 mmol) at room temperature under nitrogen. After stirring for 3 hours at room temperature, the reaction mixture was quenched with solid potassium carbonate and evaporated. The residue was chromatographed on a column of silica gel, eluting with EtOAc-Hexane=1:5 to 1:3, to give the title compound (174 mg, 43%) as white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (3H, s), 3.79 (3H, s), 4.91 (2H, s), 6.81 (1H, s), 7.05 (1H, s), 7.60-7.80 (2H, m), 7.80-8.00 (2H, m). MS (ESI) m/z not observed M+ peak.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[S:12][N:11]=[C:10](SC)[N:9]=2)[CH2:3]1.Cl[C:16]1C=C(C=CC=1)C(OO)=O.[S:26]([O-:29])(O)=[O:27].[Na+]>C(Cl)(Cl)Cl>[CH3:16][S:26]([C:10]1[N:9]=[C:8]([CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)[S:12][N:11]=1)(=[O:29])=[O:27]
Reactant: CSc1nsc(C2CCCC(C)C2)n1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1CCCC(c2nc(S(C)(=O)=O)ns2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
700 mg of 5-(3-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole was dissolved in 6 ml of chloroform, 1.73 g of 3-chloroperoxybenzoic acid (content>65%) was added thereto, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1.5 hours under room temperature. Then, the reaction mixture was added to saturated sodium hydrogensulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogencarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 784 mg of 3-methylsulfonyl-5-(3-methylcyclohexyl)-1,2,4-thiadiazole.
Reaction SMILES: [NH2:1][C:2]1([C:15]([O-:17])=[O:16])[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.[CH:18](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[NH2:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)[O-])CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 76 %

Procedure:
4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylate (5 g) in acetonitrile (22 ml) and methanol (2 ml) was treated with diisopropylethylamine (3.65 ml) and trimethylsilyldiazomethane (2M in hexane, 13.9 ml). After overnight stirring and evaporation of solvent, the crude product was chromatographed on silica gel (0–50% ethyl acetate/petrol) to give a yellow oil (4 g, 76%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CCCc1nc(-c2ccccc2C)oc1C(=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CCCc1nc(-c2ccccc2C)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C23H26N4O3 (m/e) 406, obsd 407 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H]([C@@H]([C@@H](CO)O)O)O)O.COC([C@@H](NC([C@@H](N)CC(O)=O)=O)CC1C=CC=CC=1)=O.[C:34]12([CH3:44])[C:40]([CH3:42])([CH3:41])[CH:37]([CH2:38][CH2:39]1)[CH2:36][CH:35]2[OH:43].C[C@H]1C[C@@H](O)[C@H](C(C)C)CC1>C(O)C.OCC(CO)O>[C:34]12([CH3:44])[C:40]([CH3:41])([CH3:42])[CH:37]([CH2:38][CH2:39]1)[CH2:36][C:35]2([CH2:3][CH2:2][OH:1])[OH:43]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: CC1(C)C2CCC1(C)C(O)C2
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: CCO
Solvent: OCC(O)CO
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2
Reaction time: 1 h

Procedure:
Thereafter, the warm aqueous mixture is filtered by using 100 mesh sieve and residues from the first filtration are extracted with. 20 l of water at a temperature of 80°-100° C. for 1 hour and condensed and under the reduced. Pressure to produce about 15 l of a natural substance extract. After 76.7 g of Bezoar bovis and 63.3 g of Moschus are dried on a silicagel desiccator for 24 hours and ground into microparticle size in a grinder to form a microparticle mixture by using 140 mesh sieve to make a Bezoar bovis powder and a Moschus powder, respectively. 5 Kg of conc-glycerin, 5 Kg of sugar and 35 Kg of d-sorbitol or 35 Kg of "ASPARTAME" and 10 Kg of Mel are solved with 10 l of distilled warm water for 15 minutes to make a sweetening solution. 5 l of distilled water is added to 110.0 g of genus Gelatin and the aqueous mixture is heated to produce a Gelatin solution. And 63.3 g of Borneol, and 0.5 l of L-menthol are solved with 3.5 l of ethanol to produce a Borneol-ethanol solution.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]2([CH2:12][CH:11]([CH3:13])[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8]2)CO[CH:3]=1.[H][H].[CH:18]([OH:21])(C)C>[Ni]>[CH3:1][CH:2]1[CH2:7][C:6]2([CH2:12][CH:11]([CH3:13])[CH2:10][C:9]([CH3:14])([CH3:15])[CH2:8]2)[O:21][CH2:18][CH2:3]1
Reactant: CC1=COCC2(C1)CC(C)CC(C)(C)C2
Reactant: CC(C)O
Reactant: [H][H]
Agent: [Ni]
Product: CC1CCOC2(C1)CC(C)CC(C)(C)C2
Yield: 90 %

Procedure:
A solution of 4,8,8,10-tetramethyl-2-oxaspiro [5.5] undec-3-ene (2.08 kg, 10.0 mols), isopropyl alcohol (1000 ml) and Raney nickel (100 g) or other suitable sponge-metal catalyst was hydrogenated at 400 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 4,8,8,10-Tetramethyl-1-oxaspiro[5.5] undecane (1.89 kg, yield: 90%, purity: 97% sum of the isomers).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][C@:36]([CH2:42][O:43][C:44]([F:47])([F:46])[F:45])([CH:40]=[CH2:41])[C:37]([OH:39])=[O:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:41]=[CH:40]/[C@:36]([CH3:35])([CH2:42][O:43][C:44]([F:45])([F:46])[F:47])[C:37]([OH:39])=[O:38])=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=C[C@](C)(COC(F)(F)F)C(=O)O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/[C@](C)(COC(F)(F)F)C(=O)O)cc3n2)N1
Temperature: 25 °C

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (212 mg, 0.4 mmol), crude (R)-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid (95 mg), tri(o-tolyl)phosphine (24 mg, 0.08 mmol) and triethylamine (121 mg, 0.17 mL, 1.2 mmol) in 1,4-dioxane (10 mL) was stirred at 50° C. under nitrogen. Trs(dibenzylideneacetone)dipalladium(0) (36 mg, 0.04 mmol) was added and the reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-(R)-4-{2-[(R)-1-({(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid which was used in the next step. LCMS (m/z) 652.1 [M+H], Tr=2.17 min.
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[S:2].[CH3:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>CO.C(Cl)Cl>[P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[N:30][NH:29][C:27](=[O:28])[C:26]2[CH:31]=[CH:32][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH:15]=1)([O:3][CH2:4][CH2:5][CH2:6][CH3:7])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[S:2]
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: CCCCOP(=S)(OCCCC)Oc1cccc(C=O)c1
Solvent: ClCCl
Solvent: CO
Product: CCCCOP(=S)(OCCCC)Oc1cccc(C=NNC(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O,O-dibutyl O-(3-formylphenyl) thiophosphate (0.02 mole) in methanol (50 ml) and 4-methylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O,O-dibutyl O-[3-(4-methylbenzoylhydrazonomethyl)phenyl] thiophosphate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([NH2:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[F:49][C:50]([F:62])([F:61])[O:51][C:52]1[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:12][O:11][CH2:10][CH2:9][CH:8]([NH:13][C:14]1[C:23]2[C:18](=[C:19]([C:24]([NH2:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:56](=[O:57])[C:55]2[CH:59]=[CH:60][C:52]([O:51][C:50]([F:49])([F:61])[F:62])=[CH:53][CH:54]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Reaction time: 8 h
Yield: 34.4 %

Procedure:
A mixture of 4-{[1-(3-aminophenyl)-3-methoxypropyl]amino}quinazoline-8-carboxamide (50.00 mg; 0.14 mmol; 1.00 eq.), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (30 mg; 0.16 mmol; 1.10 eq.) and 1H-1,2,3-benzotriazol-1-ol (22 mg; 0.16 mmol; 1.10 eq.) in dry DMF (1 mL) were added 4-(trifluoromethoxy)benzoic acid (33 mg; 0.16 mmol; 1.10 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.08 ml; 0.43 mmol; 3.00 eq.). The mixture was stirred overnight. After concentration, the crude was purified by reverse phase HPLC to obtain 26 mg of the title product in 34% yield. LCMS [540 (M+1)]. 1H NMR (400 MHz, DMSO-D6): 2.1875 (m, 1H), 2.3432 (m, 1H), 3.2379 (s, 3H), 3.3835 (m, 1H), 3.4522 (m, 1H), 5.7150 (m, 1H), 7.0524 (m, 2H), 7.2017 (m, 1H), 7.3317 (m, 1H), 7.6285 (m, 1H), 7.9371 (m, 6H), 8.0791 (m, 1H), 8.5544 (m, 1H), 8.6647 (s, 1H), 8.8136 (s, 1H), 10.3786 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH:8][C:9]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:12]2[O:13][C:14]([CH:18]=O)([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[CH3:24]>CO>[OH:8][C:9]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:12]2[O:13][C:14]([CH:18]3[NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]3)([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[CH3:24]
Reactant: N[C@@H](CS)C(=O)O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C=O)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C1N[C@H](C(=O)O)CS1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of cysteine (1.5 g, 12.7 mmol) and the intermediate prepared in Example 2 above, 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl methanal (3.0 g, 13 mmol), in methanol was warmed at reflux for 2.5 h. The reaction mixture was cooled to ambient temperature and then stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate was recrystallized from ethanol (3 times) to give 1.2 g (28% yield) of (4R)-2-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl)-4-thiazolidine carboxylic acid as a white solid, m.p. 184°-186° C.
Reaction SMILES: S(Cl)(Cl)=[O:2].[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:12][C:13]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:14]=1[C:15]#N.[C:25](=O)(O)[O-:26].[Na+]>CO>[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:12][C:13]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:14]=1[C:15]([O:26][CH3:25])=[O:2]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N[C@H]1CCCC[C@@H]1N
Reactant: O=C([O-])O
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)cc1N[C@H]1CCCC[C@@H]1N
Temperature: 60 °C

Procedure:
Methanol and thionyl chloride were added to 2-{[(1S,2S)-2-aminocyclohexyl]amino}-4-(trifluoromethyl)benzonitrile, followed by stirring with heating at 60° C. After neutralizing the reaction liquid by adding sodium bicarbonate aqueous solution thereto, the reaction liquid was post-treated to obtain methyl 2-{[(1S,2S)-2-aminocyclohexyl]amino}-4-(trifluoromethyl)benzoate.