Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C:27]3=[O:31])[C@H:23]3[C:14]2=[C:15]2[C:20]([CH2:21][CH2:22]3)=[CH:19][C:18](=[O:32])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1.C(OC(=O)C)(=O)C.C(Br)(=O)C>>[OH:32][C:18]1[CH:17]=[CH:16][C:15]2[C@@H:14]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][C@@H:13]3[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=3)([CH3:29])[C:27](=[O:31])[CH2:26][CH2:25]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCl)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(=O)Br
Solvent: CC(=O)OC(C)=O
Product: C[C@]12C[C@H](c3ccc(OCCCCCl)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Yield: 109629.6 %

Procedure:
The operation is carried out as in Stages B and C of Example 3 starting with 1.35 mg of the product obtained in Stage A above using 1.4 cm3 of acetic anhydride and 0.7 cm3 of acetyl bromide. 1.48 g of desired product is obtained.
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([O:52]C)=O)=[CH:31][CH:30]=1.N>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([NH2:2])=[O:52])=[CH:31][CH:30]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12
Agent: N
Product: NC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-imidazole-2-carboxylate and ammonia. 1H-NMR (CDCl3, 400 MHz, δ) 8.59 (d, J=4.4 Hz, 1H), 8.23 (d, J=9.2 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.36 (dd, J=4.4, 9.2 Hz, 1H), 6.87 (s, 1H), 6.21 (s, 2H) ppm; m/e 353 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[C:50]([O:51][CH2:52][CH2:53][NH:54][CH3:55])[C:43]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1.[C:56]([OH:60])(=O)[CH2:57][OH:58].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[C:50]([O:51][CH2:52][CH2:53][N:54]([CH3:55])[C:56](=[O:60])[CH2:57][OH:58])[C:43]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1
Reactant: O=C(O)CO
Reactant: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)C(=O)CO
Reaction time: 8 h
Yield: 99.8 %

Procedure:
HATU (52 mg) was added to a stirred solution of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-3-[2-(methylamino)ethoxy]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 60/47 mg, 0.10 mmol), glycolic acid (10 mg, 0.13 mmol) and DIPEA (60 μl) in DMF (4 ml) and the solution was stirred overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between water and DCM. Organic extracts were dried and concentrated and the residue triturated with ether to give the title compound as a white solid (50 mg, 94%); Mass Spectrum 500.8 (M+/retention time 2.18 minutes).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:12]([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:15].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][N:4]2[CH:12]([O:13][CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:15])[CH2:29][CH2:28]1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: COC1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1c2ccccc2C(=O)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 10 h
Yield: 21.4 %

Procedure:
The procedure is as in Example 25, starting with (RS)-2-(2-bromoethyl)-3-methoxyisoindolinone (2.4 g), 4-[(5-fluoro-3-indolyl)methyl]piperidine (2.1 g) and sodium bicarbonate (0.74 g) in a mixture of dimethylformamide (50 cc) and tetrahydrofuran (40 cc). The mixture is heated to boiling for 10 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with ethyl acetate as eluent, and recrystallization a first time in acetonitrile (40 cc) and then in methyl ethyl ketone (35 cc), (RS)-2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-3-methoxyisoindolinone (0.8 g), m.p. 175° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:16](Cl)(=[O:18])[CH3:17]>C1C=CC=CC=1>[C:16]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Fc1ccc2c(c1)Sc1ccccc1N2
Solvent: c1ccccc1
Product: CC(=O)N1c2ccccc2Sc2cc(F)ccc21
Yield: 86.1 %

Procedure:
108 grams of 3-fluorophenothiazine were dissolved in 1 liter of dry benzene. 75 grams of acetyl chloride were then added and the mixture heated under reflux for 4 hours, whereupon the mixture was evaporated. The residue was recrystallized from ethanol and 111 grams of 10-acetyl-3-fluorophenothiazine were obtained. MP: 125° Centigrade. The 111 grams of 10-acetyl-3-fluorophenothiazine were heated under reflux for 2 hours with 160 grams of anhydrous aluminium chloride in 800 milliliters of carbon disulphide. The mixture was cooled, and 70 grams of acetyl chloride were added slowly, whereupon the mixture was heated under reflux for 4 hours. The mixture was poured onto crushed ice and extracted with ether. The ether phase was evaporated, the residue dissolved in a mixture of 2 liters of ethanol and 50 milliliters of 50% sodium hydroxide solution and heated for 5 minutes on a steam bath. Thereby 2-acetyl-7-fluorophenothiazine crystallized out as white crystals which melt at 210° Centigrade. Yield: 80 grams.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[O-]S([O-])(=O)=O.[Na+].[Na+]>CO.[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1OC
Yield: 100.3 %

Procedure:
The hydrogenation of methyl 2-methoxy-4-nitrobenzoate (700 mg, 3.3 mmol) in methanol (10 mL) catalyzed by 5% Pd—C (100 mg) and Na2SO4 (100 mg) at 50 psi for 1 h gave methyl 4-amino-2-methoxybenzoate (600 mg, quant.) as a white solid.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]#[CH:7])[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOC(C)=O.[Cl-].[Na+].O>[CH2:14]([O:21][C:22](=[O:23])[N:4]([CH2:5][C:6]#[CH:7])[CH2:1][C:2]#[CH:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C#CCNCC#C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCN(CC#C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of dipropargylamine (46.7 g, 502 mmol) in EtOAc (200 mL) and 10% aqueous K2CO3 (700 mL, 507 mmol) was slowly added a solution of N-(benzyloxycarbonyloxy)succinimide (125 g, 502 mmol) in EtOAc (500 mL) over 20 mins. The solution was stirred at 0° C. for 2 h then at RT 16 h. The phases were separated and the organic phase was washed with 10% aqueous K2CO3 (700 mL, 507 mmol) and then with saturated brine (500 mL) and was diluted to 1000 mL with EtOAc to give a 0.5M solution.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][S:37]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:43]2[CH:44]=[CH:45][C:40]([S:37]([CH3:36])(=[O:39])=[O:38])=[CH:41][CH:42]=2)=[CH:21][CH:22]([CH3:23])[CH3:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C=C(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(F)cnc2n1S(=O)(=O)c1ccccc1
Yield: 90.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (1 g, 2 mmol), 4-(methanesulfonyl)phenylboronic acid (1 g, 5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (140 mg, 0.2 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridine (0.9 g, 92%) as a white solid: LC/MS m/e calcd for C25H23FN2O4S2 [M+H]+ 499.60, observed 498.8.
Reaction SMILES: [CH2:1]([C@@:5]12[C@H:20]([CH2:21][CH2:22][CH3:23])[C:19](=[O:24])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14]COC)=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C@@:5]12[C@H:20]([CH2:21][CH2:22][CH3:23])[C:19](=[O:24])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12Cc3cc(OCOC)ccc3C1=CC(=O)[C@H]2CCC
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC[C@]12Cc3cc(O)ccc3C1=CC(=O)[C@H]2CCC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of (rac)-(1S,8aR)-8a-butyl-6-(methoxymethoxy)-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (92 mg, 0.28 mmol) in methanol (1 mL) was treated with aqueous 2N HCl (0.42 mL, 0.84 mmol). The resulting mixture was stirred and gradually heated to 80° C. over 30 minutes, and then kept at 80° C. for an additional 30 minutes. After cooling, the mixture was diluted with EtOAc and washed with 5% NaHCO3. The aqueous portion was back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12S (1.2×7.5 cm) silica gel column, eluting with 5:1 hexane-EtOAc, to give (rac)-(1S,8aR)-8a-butyl-6-hydroxy-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as a white solid.
Reaction SMILES: [OH-].[K+].Cl.CN.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH3:21])([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22]([BH3-])#[N:23].[Na+]>CO>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:23][CH3:22])[C:15]([CH3:21])([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [BH3-]C#N
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1(C)C
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (12.85 g, 230 mmol) was added to the stirred solution of methylamine hydrochloride (15.5 g, 230.0 mmol) in methanol (100 ml) and stirring was continued for 30 min at 30° C. 1-Benzyl-3,3-dimethyl-4-piperidone (5 g, 23.0 mmol), was added to the resulting mixture and stirred for 6 hr. Sodium cyanoborohydride (1.45 g, 23.0 mmol) was added to it and reaction mixture was stirred for 15 hr. The reaction mixture was concentrated to dryness, triturated with water, extracted with chloroform, dried (Na2SO4) and concentrated to give 1-benzyl-4-methylamino-3,3-dimethylpiperidine. Yield 5.3 g (99%), C15H24N2, m/z 223 (M+1), PMR (CDCl3): 0.9 (s, 3H), 1.0 (s, 3H), 1.38 (m, 2H), 1.54 (bs, 1H, D2O exchangeable), 1.68-2.1 (m, 4H), 2.4 (s, 3H), 2.86 (m, 1H), 3.4 (dd, 2H), 7.3 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]CC2C=CC(OC)=CC=2)=[CH:6][C:5]([Cl:18])=[CH:4][C:3]=1[O:19][CH3:20].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([Cl:18])=[CH:6][C:7]=1[SH:8]
Reactant: COc1ccc(CSc2cc(Cl)cc(OC)c2Cl)cc1
Solvent: COc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)cc(S)c1Cl
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
The mixture of 2,5-dichloro-1-methoxy-3-((4-methoxybenzyl)sulfanyl)benzene (5.56 g) and anisole (9.18 mL) was added TFA (22.13 mL) at room temperature. The mixture was stirred at 80° C. for 20 min. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was extracted with 1N NaOH. The aqueous layer was acidified with 1N HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (2.38 g).
Reaction SMILES: [CH3:1][N:2]([S:11]([CH3:14])(=[O:13])=[O:12])[C:3]1[O:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:15][C@@H:16]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([F:38])[CH:34]=1)[CH2:30][C@H:16]([NH:15][C:8]([C:6]1[N:7]=[C:3]([N:2]([CH3:1])[S:11]([CH3:14])(=[O:13])=[O:12])[O:4][CH:5]=1)=[O:10])[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1
Reactant: CN(c1nc(C(=O)O)co1)S(C)(=O)=O
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2coc(N(C)S(C)(=O)=O)n2)c1
Reaction time: 2 h

Procedure:
To a 7 ml screw cap vial was added (20.9 mg, 0.0949 mmoles) 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylic acid, (36.7mg, 0.1097 mmoles, 1.15 eq.) (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol and (54.6 mg, 0.1436 mmoles, 1.5 eq.) HATU, followed by (1.25 ml) N,N-dimethylformamide. The reaction was placed in an orbital shaker and was left at ambient temperature for 2 hours. The reaction was quenched with (2 ml) 1N HCl. The clear solution was extracted three times with ethyl acetate and the combined organic layers were washed with saturated sodium carbonate solution and then brine. The solution was then dried with magnesium sulfate and evaporated to a clear oil which was purified by preparative HPLC, resulting N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide (15.7 mg).
Reaction SMILES: [N:1]([C@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:23][CH2:22][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[N+]=[N-].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:1][C@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CC1=C(N2CCC3(CCN(C[C@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(N2CCC3(CCN(C[C@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-8-(2-azido-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (250 mg, 0.54 mmol) in a mixed solvent of tetrahydrofuran and water (v:v, 12:1, 20 mL) was added triphenylphosphine (283 mg, 1.08 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation and the residue was purified by preparative TLC (dichloromethane: methanol=10:1) to afford the title compound. 1H NMR (400 MHz, Methanol-d4): δ 7.80 (d, J=8.0 Hz, 1H), δ 7.66 (d, J=8.0 Hz, 1H), 5.40 (s, 2H), 5.24 (s, 2H), 4.73 (dd, J=4.0 Hz, 8.8 Hz, 1H), 4.09 (t, J=6.8 Hz, 2H), 3.30-3.21 (m, 1H), 2.98-2.91 (m, 1H), 2.87-2.81 (m, 1H), 2.70-2.66 (m, 1H), 2.55-2.47 (m, 2H), 2.40 (s, 3H), 2.18-2.07 (m, 4H), 2.00 (s, 3H), 1.74-1.68 (m, 2H). MS-ESI (m/z): 440 (M+1)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH:10]([CH:12]([C:14]([O-])=O)[OH:13])O)([O-])=[O:8].[K+].[Na+].O1[CH2:23][CH2:22][CH2:21]C1>>[CH:21]1([CH2:14][CH:12]([OH:13])[CH2:10][CH2:7][OH:8])[CH2:22][CH2:23]1
Reactant: C1CCOC1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Product: OCCC(O)CC1CC1
Reaction time: 2.5 h

Procedure:
A solution of 3.23 g (13.91 mmol) of the title compound in step (i) of Example XA1 in tetrahydrofuran (31.3 ml) was cooled to 0° C. Lithiumaluminum hydride (2.11 g, 55.62 mmol) was then added thereto, and the mixture was stirred for 2.5 hr. Thereafter, the reaction solution was stirred at room temperature for one hr. Lithium aluminum hydride (0.528 g, 13.91 mmol) was added thereto, and the mixture was stirred at room temperature for one hr. A saturated aqueous sodium potassium tartrate solution was added thereto, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated at a low temperature under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:diethyl ether=1:1 to 1:4) to give the title compound as a crude product.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19].O>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:26])[C:22]([NH:11][CH:8]1[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)([CH3:24])[CH3:23])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CS(=O)(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NC1CCN(S(C)(=O)=O)CC1
Reaction time: 16 h
Yield: 14.2 %

Procedure:
2.40 g (13.5 mmol) of 1-methanesulfonyl-piperidin-4-ylamine are dissolved in DMF (32.8 mL). 5.58 g (40.4 mmol) of K2CO3, 3.06 mL (20.2 mmol) ethyl-2-bromoisobutyrate and 1.12 g (6.73 mmol) of KI are added at RT. The reaction is stirred 16 h. Additional ethyl-2-bromoisobutyrate (3.06 mL) and KI (1.12 g) are added and the reaction mixture is stirred for further 16 h. Water and sat. aq. K2CO3 solution is added, the aqueous layer extracted with EE. The combined organic layers are dried over MgSO4 and filtered. The solvent is removed under reduced pressure to afford the crude product, which is purified by silica gel chromatography (eluent: EE/MeOH 95/5) to afford 0.56 g of 2-(1-methanesulfonyl-piperidin-4-ylamino)-2-methyl-propionic acid ethyl ester. Yield: 14%; ESI-MS: 293 [M+H]+; HPLC (Rt): 0.97 min (method E)
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.CC1C=CC(S(NC2C=C(S([O-])(=O)=O)C=C3C=C(S([O-])(=O)=O)/C(/C(=O)C=23)=N/NC2C=C(Cl)C=CC=2OC2C=CC=CC=2)(=O)=O)=CC=1.[Na+].[Na+].[OH-].[Na+]>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Agent: Cc1ccc(S(=O)(=O)Nc2cc(S(=O)(=O)[O-])cc3c2C(=O)/C(=N\Nc2cc(Cl)ccc2Oc2ccccc2)C(S(=O)(=O)[O-])=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Reaction time: 5 h

Procedure:
20 g of C.I. pigment red 122 having an average primary particle diameter of 90 nm (in which the content of metal ion having a valence of at least 2 was 450 ppm), 4 g of a commercially available dye C.I. acid red 249 and 110 g of deionized water were mixed, a 1% by weight sodium hydroxide aqueous solution was added so as to adjust the pH of a mixture liquid to 9.0, and the mixture liquid was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 5 hours, to obtain a water-based pigment dispersion. The obtained water-based pigment dispersion had a high viscosity and caused flocculation. Further, the water-based pigment dispersion was diluted so as to have a concentration of 3% by weight, and the diluted water-based pigment dispersion was dropped on No.2 filter paper, to show bleeding of the dye.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C@H:16]1[O:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.ClCCl>[CH3:22][C@H:20]1[O:21][C@@H:16]([CH3:15])[CH2:17][N:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:19]1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(-c3ccc(O)cc3)cc2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 4-bromo-4′-hydroxy-1,1′-biphenyl (5 g), cis-2,6-dimethylmorpholine, dichlorobis(tri-o-tolylphosphine)-palladium(II) and lithium bis(trimethylsilyl)amide (1.0 M solution in hexanes) (44 ml) in toluene (25 ml) was stirred for 6 hours at 100° C. The reaction mixture was added to a mixture of 1.0 mol/l hydrochloric acid and dichloromethane. The organic layer was washed with 1.0 mol/l hydrochloric acid, sodium hydrogen carbonate solution and sodium chloride solution. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (50:1 dichloromethane-methanol elution) to give 4′-(cis-2,6-dimethylmorpholin-4-yl)-1,1′-biphenyl-4-ol (1.49 g).