Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:12]2=[C:13]([N:20]3[CH2:23][CH2:22][C@H:21]3[CH2:24][OH:25])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:32]COC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:12]2=[C:13]([N:20]3[CH2:23][CH2:22][C@H:21]3[CH2:24][O:25][CH3:32])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC[C@H]3CO)c2CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H]1CCN1c1c2c(nc3ccnn13)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To 57.9 mg (0.155 mmol) (S)-10-(2-hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 10 mL anhydrous THF was added 29.8 mg (1.24 mmol, 60% dispersion in mineral oil) NaH and the reaction was cooled to 0° C. 0.4 mL (1.24 mmol) methyl iodide was added and the reaction was stirred at room temperature for 6 hours. 25 mL EtOAc was added and the organic layer was washed with H2O (2×20 mL), 20 mL saturated brine, and dried over MgSO4. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 2:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[F:12][C:13]([F:23])([F:22])[C:14](=O)[CH2:15][C:16](OCC)=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([OH:17])[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=2)[N:5]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(N)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(OC)c2nc(C(F)(F)F)cc(O)c2c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
2,4-Dimethoxyaniline (30 g) was dissolved in benzene (400 mL), and ethyl trifluoroacetoacetate (34 mL) and p-toluenesulfonic acid monohydrate (3.7 g) were added. The mixture was refluxed for 21 hr. The reaction solution was concentrated under reduced pressure, and a saturated a aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract solution washed with saturated brine, dried and concentrated under reduced pressure. 75% Polyphosphoric acid (150 mL) was added to the residue and the mixture was stirred at 130° C. for 2 hr. The reaction solution was poured onto ice, and the mixture was extracted with ethyl acetate. The extract solution washed successively with a saturated a aqueous sodium hydrogen carbonate solution, 1 mol/L hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. Ethanol was added to the residue and the precipitate was filtered off. The filtrate was concentrated under reduced pressure to give 2-trifluoromethyl-4-hydroxy-6,8-dimethoxyquinoline (12 g) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:7]=[CH:6][C:5]=1[Cl:16].[OH-].[K+].CO.Cl>CO>[Cl:16][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(-c2cc(C)[nH]n2)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2ccc(Cl)c(C(=O)O)c2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
A solution of 2-chloro-5-(5-methyl-1H-pyrazol-3-yl)-benzoic acid methyl ester (4.5 g, 17.0 mmol) in methanol (20.0 mL) was treated with potassium hydroxide (4.52 g, 80.0 mmol). The mixture was stirred at room temperature for 16 h. The mixture was acidified to pH 4.0 with conc. HCl Methanol was removed from the mixture under vacuo. The residue was stirred at rt for 2 h and the solids collected by filtration, washed with water, 2:1 Hexanes/ether and dried to give the title compound (2.2 g)
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][CH:34]([NH2:37])[CH2:35][OH:36]>>[OH:36][CH2:35][CH:34]([NH:37][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:33]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: CC(N)CO
Product: CC(CO)Nc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and DL-2-amino-1-propanol. White solid. MS (ESI): 529.3 (MH+).
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][OH:17])[CH2:11]1)C1C=CC=CC=1.[ClH:18].[H][H]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:18].[NH:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][OH:17])[CH2:11]1
Reactant: [H][H]
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: OCC1CNCCO1

Procedure:
In an autoclave under an argon atmosphere at ambient temperature (20° C.), 215 ml of methanol, 1.7 g of palladium hydroxide (12135-22-7), 12.4 g of (4-benzylmorpholin-2-yl)methanol and 15 ml of 4M HCl are successively placed in dioxane. After the autoclave has been closed, the reaction medium is placed under 6 bar of hydrogen at 25° C. for 24 h. The reaction medium is filtered through Clarcel, rinsed several times with methanol; the filtrate is concentrated under reduced pressure. Morpholin-2-ylmethanol hydrochloride (9.65 g) is isolated in the form of a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(CO)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
12.67 g (14.6 nunol) of manganese dioxide were added to a solution of 3.45 g (7.35 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-hydroxymethyl-2-methoxyphenyl)octanamide (prepared as described in Preparation 61) in 40 ml of methylene chloride, and the resulting mixture was vigorously stirred at room temperature for 10 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure to give the title compound as a foam-like substance in a 86% yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:34]2[N:39]=[CH:38][C:37]([C:40]([OH:42])=O)=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)[CH3:26].CCN(C(C)C)C(C)C.[F:52][C:53]([F:66])([F:65])[C:54]1[NH:55][C:56]2[C:61]([CH:62]=1)=[CH:60][C:59]([CH2:63][NH2:64])=[CH:58][CH:57]=2>CN(C=O)C>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:34]2[N:39]=[CH:38][C:37]([C:40]([NH:64][CH2:63][C:59]3[CH:60]=[C:61]4[C:56](=[CH:57][CH:58]=3)[NH:55][C:54]([C:53]([F:66])([F:52])[F:65])=[CH:62]4)=[O:42])=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)[CH3:26]
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: CCOc1cccc(-c2ccc(C(=O)O)cn2)c1
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: CCOc1cccc(-c2ccc(C(=O)NCc3ccc4[nH]c(C(F)(F)F)cc4c3)cn2)c1
Reaction time: 24 h
Yield: 64 %

Procedure:
To a stirred solution of HATU (72.8 mg, 0.192 mmol) in DMF (1 ml) was added 6-[3-(ethyloxy)phenyl]-3-pyridinecarboxylic acid (Intermediate 6, 29 mg, 0.119 mmol) in DMF (0.5 ml), followed by DIPEA (0.050 ml, 0.287 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 24 mg, 0.096 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge. The organic layer was evaporated to dryness and purified using MDAP to give the title compound as a white solid (27 mg);
Reaction SMILES: [CH:1]1([C:4]2([CH:24]3[CH2:26][CH2:25]3)[CH:8]3[CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19]C=4)=[O:14])[CH2:11][CH2:12][N:7]3[C:6](=[O:23])[O:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)OC1C=CC=CC=1.O>C(O)C.[C].[Pd]>[CH:24]1([C:4]2([CH:1]3[CH2:3][CH2:2]3)[CH:8]3[CH2:9][N:10]([C:13]([O:15][C:16]4[CH:17]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:14])[CH2:11][CH2:12][N:7]3[C:6](=[O:23])[O:5]2)[CH2:26][CH2:25]1
Reactant: O=C(OCc1ccccc1)N1CCN2C(=O)OC(C3CC3)(C3CC3)C2C1
Agent: [Pd]
Agent: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N1CCN2C(=O)OC(C3CC3)(C3CC3)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
(Phenylmethyl) 1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (0.18 g, 0.50 mmol) was dissolved in ethanol (10 mL). 10% Palladium carbon (17 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through Celite, the Celite was washed with ethanol, and the filtrate was concentrated under reduced pressure. The resulting 1,1-dicyclopropyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one was dissolved in tetrahydrofuran (10 mL). Triethylamine (0.14 mL, 0.99 mmol) and phenyl chlorocarbonate (90 μL, 0.74 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=7:1 to 1:1) and recrystallized from diisopropyl ether-hexane to obtain the title compound (0.15 g, 88% yield (phenylmethyl) 1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6](S(NC)(=O)=O)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18].N([O-])=O.[Na+].[I-:28].[K+].CCOC(C)=O>S(=O)(=O)(O)O.O>[I:28][C:7]1[C:2]([Cl:1])=[C:3]([NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18])[CH:4]=[CH:5][CH:6]=1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@](O)(C(=O)Nc1cccc(I)c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
To a cooled solution of (R)-N-[3-amino-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 8) (12.5 g) in concentrated sulphuric acid (25 ml) and water (70 ml) was added a solution of sodium nitrite (3.15 g) in water (70 ml) dropwise. The reaction mixture was allowed to stir for 10 minutes and for 1 hour at ambient temperature. A solution of potassium iodide (22.2 g) in water (70 ml) was added cautiously and the mixture was heated to 100° C. for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature, EtOAc (500 ml) was added and the organic phase was washed with brine (300 ml) and dried. Volatile material was removed by evaporation and the residue was purified by flash column chromatography eluting with 5-20% EtOAc/isohexane to give the title compound (13.5 g) as a cream solid. NMR (CDCl3) 1.76 (s, 3H), 3.63 (s, 1H), 7.05 (t, 1H), 7.68 (d, 1H), 8.36 (d, 1H), 8.97 (brs, 1H); m/z: 392.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH2:33]1[O:41][CH:34]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(C)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:33][OH:41])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: c1ccc(C2CO2)cc1
Solvent: CC(C)O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(CO)c1ccccc1

Procedure:
Cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.075 g, 0.000172 mol) and styrene oxide (0.029 g, 0.000172 mol) were dissolved in isopropanol (3 mL) and the resulting mixture was heated at reflux for 24 hours. The solvent was removed and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyanilino)-2-phenyl-1-ethanol (0.005 g, 0.0000089 mol) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]1([CH:19]=[CH:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC1C=CC=CC=1OC.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][S:21](/[CH:20]=[CH:19]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:22])=[O:23])=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: COc1cc(Br)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COc1ccccc1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C(=O)NS(=O)(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-bromo-2-methoxy-benzoic acid (159 mg, 0.69 mmol) and 2-phenyl-ethenesulfonic acid amide (108 mg, 0.59 mmol) (which was prepared analogously to example 1-1 steps i) to iii) starting from iodoanisole) in dichloromethane (5 mL) and N,N-dimethylformamide (DMF) (2 mL) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI) (170 mg, 0.89 mmol) and 4-(dimethylamino)-pyridine (DMAP) (89 mg, 0.73 mmol) at RT. The mixture was stirred at RT for 20 h, and solvent removed under reduced pressure. The crude reaction mixture is partitioned between water (15 mL) and ethyl acetate (15 mL). The organic phase is separated and washed with aq. 1M HCl (4×10 mL), and the aqueous phases combined and back extracted with ethyl acetate (3×10 mL). The organic phases were combined and washed with water (15 mL), brine (2×10 mL) and dried (sodium sulfate) and concentrated in vacuo. After flash chromatography (CH2Cl2/MeOH 10:1) (E)-2-phenyl-ethenesulfonic acid 4-bromo-2-methoxy-benzoylamide can be isolated as a white solid. Yield 65 mg (24%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][CH:22]([OH:34])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:18][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a solution (10 ml) of 0.6 g of lithium aluminum hydride (0.6 g) in tetrahydrofuran was added 0.6 g of the 1-benzyl-4-[2-(4-pyrrolidinobenzoyl)ethyl]piperidine synthesized in Example 59 and the mixture was stirred at room temperature for 30 minutes. Then, water was added cautiously thereto for decomposing the excess reagent and the reaction product was then extracted into dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude crystals. Recrystallization from ether-hexane yielded 0.5 g of colorless crystals melting at 93°-95° C.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:23]=[O:24].Cl>O.CO>[OH:24][CH2:23][C:19]1[CH:20]=[CH:21][C:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][C:18]=1[OH:22]
Reactant: C=O
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCc1ccc(CO)c(O)c1
Yield: 19.4 %

Procedure:
(2 1) 150 g of 3-pentadecylphenol and 17.7 g of paraformaldehyde were dispersed in 300 ml of water and 150 ml of methanol, and the dispersion was stirred at 50° C. for 12 hours. The reaction mixture was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 300 ml of hexane were added to the residue to precipitate a crystal. The crystal was recovered by filtration and dried to obtain 32 g of 2-hydroxymethyl-5-pentadecylphenol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:18]=2[CH3:28])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:29][N:30]([C:4]([C:3]1[CH:7]=[CH:8][C:9]([NH:11][CH:12]([C:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:18]=2[CH3:28])[CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:10][C:2]=1[CH3:1])=[O:5])[CH2:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)CCNC
Reactant: Cc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)N(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution of 2-methyl-4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}benzoic acid (245 mg), ethyl 3-(methylamino)propanoate (102 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg), hydroxybenzotriazole monohydrate (119 mg) and triethylamine (109 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.2 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (251 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[CH:19]=1>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:20]4[CH:19]=[C:18]([CH3:17])[CH:23]=[CH:22][N:21]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)c1
Temperature: 120 °C
Yield: 87.2 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.512 mmol), 4-methyl-2-tributylstannanylpyridine (235 mg, 0.614 mmol), Pd2(PPh3)2Cl2 (36 mg, 0.051 mmol) and copper iodide (29 mg, 0.153 mmol) in DMF (4 mL) was purged with nitrogen and then heated at 120° C. for 45 min using microwave irradiation. The reaction mixture was diluted with MeOH (30 mL) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by Si-PCC, gradient 0-3% MeOH in EtOAc) affording 9-Bromo-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (159 mg, 87%). LCMS: RT 2.44 min [M+H]+ 355.9/357.8
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH:11](Cl)([CH3:13])[CH3:12].[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cl
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.05 g (0.001 mol (corresponding to 1% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 4.7 g (0.060 mol) of isopropyl chloride and 1.7 g (0.072 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 20 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 8.2 g (purity: 95.0%) of the aimed di-tert-butylisopropylphosphine as an oily substance. The yield was 92.7%.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:12][C@H:9]1[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ncccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](Oc2ncccn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cis/trans-4-(pyrimidin-2-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:2) (0.35 g, 1.4 mmol) in 1,4-dioxan (7 ml) was added 2 M aqueous sodium hydroxide solution (7.0 ml, 14 mmol). Stirring at room temperature for 16 h was followed by acidification to pH 2-3 with 0.5 M aqueous hydrogen chloride solution (50 ml) and extraction with three 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (0.26 g, 83%) as yellow oil.