Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(C(C)C)CC)(C)C>O1CCOCC1.CS(C)=O>[CH2:28]([O:27][C:25](=[O:26])[NH:23][C:19]1[N:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:10]3=[N:11][O:12][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)=[C:9]3[CH:16]=2)[CH:22]=[CH:21][N:20]=1)[CH3:29]
Reactant: Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a stirring solution of 4-[3-(3-bromophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine (75 mg; 0.205 mmol) in 1 mL of p-dioxane and 0.5 mL of DMSO, was added 40 μL (45.6 mg, 0.42 mmol) of ethyl chloroformate followed by 73 μL (54.3 mg, 0.42 mmol) of diisopropylethylamine. The reaction was stirred at 50° C., in a sealed vessel, for 8 hours. The solvents were removed under vacuo and the crude material was purified via HPLC with acetonitrile/water/TFA as the eluent. The material was isolated as a yellow powder (30 mg, 32% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.5 (br s,1H), 8.9 (s, 1H), 8.75 (d, 1H), 8.35 (m, 3H), 8.3(s, 1H), 8.0 (d, 1H), 7.89 (t, 2H), 7.65 (t, 1H), 4.2 (q, 2H), 1.26 (t, 3H) in ppm. LC-MS (ES+) m/e=439/441 (M+H)
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.B(O)O>>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: Fc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 3-fluorophenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:18]1[CH:23]=[CH:22][C:21]([O:24][C:25](Cl)=[S:26])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]1([O:24][C:25](=[S:26])[O:17][CH:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: N#Cc1ccc(C(O)c2cccnc2)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(C(OC(=S)Oc2ccccc2)c2cccnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoro-4-(hydroxy-pyridin-3-yl-methyl)-benzonitrile (as described in Example 20, Step C) (0.4 g, 1.75 mmol) in CH2Cl2 (25.0 mL) at 0° C. was added phenyl thionochloroformate (0.388 mL, 2.8 mmol) and DMAP (0.471 g, 3.86 mmol). The solution was stirred at 25° C. for 3 hr. The reaction was partitioned with saturated NaHCO3 and CH2Cl2. The CH2Cl2 layer was washed with brine, dried with MgSO4, and evaporated in vacuo to obtain the title compound after chromatography (silica gel, CH2Cl2:MeOH 99:1).
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>C1COCC1.O>[CH2:16]([NH:17][C:2](=[O:3])[O-:4])[CH3:15].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: CCOC(=O)Cl
Agent: COc1ccc2c(c1)C1CNCC1C2C
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen sodium carbonate (11.7 g, 139 mmol) and ethyl chloroformate (3.2 mL, 33.4 mmol) were added to a solution of 5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 1, Step E) (5.6 g, 27.8 mmol) in THF/H2O (140 mL, 1/1, v/v), and stirred overnight at room temperature. The reaction mixture was quenched by addition of an aqueous HCl solution (200 mL, 1.0 M) and the product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 2.7 g (35%) of the subtitle compound. 1H NMR (CDCl3 300 MHz)*7.07 (d, 1H), 6.78 (m, 2H), 4.09 (m, 2H), 3.79 (m, 5H), 3.63 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26 (m, 6H) ppm. MS calculated for C16H21NO3+H: 276, observed: 276.
Reaction SMILES: C([O:3][CH2:4][C:5]([O:7][C:8]([CH:11]1[CH2:16][CH2:15][C:14]([O:18][C:19](=[O:24])[CH2:20][O:21]C=O)([CH3:17])[CH2:13][CH2:12]1)([CH3:10])[CH3:9])=[O:6])=O>C(=O)(O)[O-].[Na+]>[OH:3][CH2:4][C:5]([O:7][C:8]([CH:11]1[CH2:16][CH2:15][C:14]([O:18][C:19](=[O:24])[CH2:20][OH:21])([CH3:17])[CH2:13][CH2:12]1)([CH3:10])[CH3:9])=[O:6]
Reactant: CC1(OC(=O)COC=O)CCC(C(C)(C)OC(=O)COC=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(OC(=O)CO)CCC(C(C)(C)OC(=O)CO)CC1
Reaction time: 72 h

Procedure:
The crude product (110) was combined with aqueous sodium bicarbonate solution (20 mL, 0.75 N) and stirred for 3 days. The compound was then extracted using ethyl acetate in three 20 mL portions. The organic phase was then evaporated and separated in a column to get a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.21 (m, 8H), 1.40 (s, 6H), 1.53 (s, 3H), 2.00 (m, 1H), 2.19 (s, 1H), 2.21 (s, 1H), 3.98 (s, 2H), 4.01 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([OH:3])=[O:2].Cl[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1>C([O-])([O-])=O.[K+].[K+].C(#N)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.[Pd]>[Cl:20][C:19]1[C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1B(O)O
Reactant: Clc1cccnc1Cl
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Temperature: 90 °C

Procedure:
Tetrakis palladium (0.1 2 g, 0.1 mMol) was added to a suspension of carboxybenzene boronic acid (0.33 g, 2.0 mMol) and 2,3-dichloropyridine (0.296 g, 2.0 mMol) in a mixture of 0.4M K2CO3 (10 mL) and acetonitrile (10 mL) and the mixture was heated at 90° C. for 12 hrs under a blanket of nitrogen. The hot suspension was filtered, the filtrate concentrated to about half the original volume before being washed with methylene chloride. The aq. layer was carefully acidified with conc. HCl and the precipitate was collected, washed with water and vacuum dried to obtain the product as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[N:35]=[C:36]=[O:37])([CH3:25])[CH3:24]>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:36]([NH:35][C:27]1[C:26]([CH:23]([CH3:24])[CH3:25])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccccc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-octylphenyl)amine and 2,6-diisopropylphenyl isocyanate as starting materials, N-benzyl-N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)urea is obtained.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][S:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27](O)[CH3:28]>S(=O)(=O)(O)O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][S:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=3)[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 80 %

Procedure:
To a mixture of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionic acid (365 mg) and ethanol (10 ml) was added concentrated sulfuric acid (one drop) and heated for 4 hours under reflux. The reaction mixture was concentrated, to which was added saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of ethyl 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionate (310 mg, 80%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 77-78° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[SH:25]>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:17]2[N:16]([CH3:15])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Cn1c(S)nc2ccccc21
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: Cn1c(SCC(=O)N2CCCc3ccccc32)nc2ccccc21
Yield: 77 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 1-methyl-1H-benzo[d]imidazole-2-thiol as the nucleophile to yield 17 as a pale yellow solid (77%): MS m/z: 338 (M+H)+. Anal. Calcd. For, C19H19N3OS: C, 67.63; H, 5.68; N, 12.45; S, 9.50. Found: C, 67.45; H, 5.74; N, 12.25; S, 9.41.
Reaction SMILES: C(O[C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH:18]([OH:28])[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])C1C=CC=CC=1.COC1C(O)=CC=CC=1.C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>[Pd]>[C:24]([Si:21]([O:20][CH2:19][CH:18]1[CH2:17][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=2[O:28]1)([CH3:22])[CH3:23])([CH3:25])([CH3:26])[CH3:27]
Reactant: COc1cccc(CC(O)CO[Si](C)(C)C(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: COc1ccccc1O
Solvent: Oc1ccccc1
Product: COc1cccc2c1OC(CO[Si](C)(C)C(C)(C)C)C2
Yield: 80.5 %

Procedure:
Treatment of (±)-1-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (58.14 g, 0.144 mol) with palladium on carbon (5.81 g, 10 wt. %) generally according to the procedure described for Intermediate 4 provided (±)-2-(3-[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-6-methoxyphenol as a crude oil. Treatment of the phenol with triphenylphosphine (44.52 g, 0.170 mol) and diethylazodicarboxylate (29.56 g, 0.170 mol) generally according to the procedure described for Intermediate 5 gave 34.12 g (80%) of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane as a colorless oil. Rf=0.67 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C16H26O3Si: C, 65.26; H, 8.90. Found: C, 64.26; H, 9.24.
Reaction SMILES: [CH2:1]([C:8]1([N:28]([CH3:30])[CH3:29])[CH2:13][CH2:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=3)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([C:8]1([N:28]([CH3:30])[CH3:29])[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C2=CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(C(F)(F)F)cc12
Agent: [Pd]
Solvent: CO
Product: Cc1c(C2CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(C(F)(F)F)cc12
Reaction time: 4 h

Procedure:
(±)-[1-Benzyl-4-(3-methyl-5-trifluoromethyl-1H-indol-2-yl)cyclohex-3-enyl]-dimethylamine (220 mg, 0.53 mmol) was dissolved in methanol (50 ml), while heating, and Pd/C (5%, 100 mg) was added under argon. Hydrogenation was carried out at 40° C. under 3 bar for 4 h. The catalyst was then filtered off with suction over Celite and the filtrate was concentrated. The solid colourless residue was separated by chromatography [silica gel 60 (30 g); ethyl acetate/methanol (20:1; 500 ml); (4:1; 300 ml); (2:1; 300 ml)]. N-[1-Benzyl-4-(3-methyl-5-trifluoromethyl-1H-indol-2-yl)cyclohexyl]-N,N-dimethylamine (less polar diastereoisomer) was isolated in a yield of 46 mg (21%) as a colourless solid with a melting point of 180-210° C. The polar diastereoisomer was obtained in a yield of 152 mg (69%) as a colourless solid with a melting point of 166-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(Br)cc1
Product: COC(=O)C(=O)Nc1ccc(Br)cc1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-bromoaniline and methyl chlorooxoacetate.
Reaction SMILES: [I-].[CH:2]([NH:4][C:5]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:6]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[CH3:15])=[O:3].[I-].[N+](C1C=CC=CC=1C=CC1C=CC=C[N+]=1C)([O-])=O>>[CH:2]([NH:4][C:5]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:6]=1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH3:15])=[O:3]
Reactant: COc1ccc(NC=O)c(CCc2cccc[n+]2C)c1
Agent: C[n+]1ccccc1C=Cc1ccccc1[N+](=O)[O-]
Agent: [I-]
Product: COc1ccc(NC=O)c(CCC2CCCCN2C)c1

Procedure:
Catalytic reduction of 2-(2-formamido-5-methoxyphenethyl)-1-methylpyridinium iodide as described in Example 1 for 2-(o-nitrostyryl)-1-methylpyridinium iodide provides 2-(2-formamido-5-methoxyphenethyl)-1-methylpiperidine. This material is deformylated in 1N methanolic hydrogen chloride providing 2-(2-amino-5-methoxyphenethyl)-1-methylpiperidine.
Reaction SMILES: Br[CH2:2][CH3:3].[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:3]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(O)c2ccccc2c1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1O
Yield: 60.5 %

Procedure:
Bromoethane (0.359 g, 3.29 mmol) was added to a stirred solution of diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate (1 g, 3.29 mmol) and potassium carbonate (0.454 g, 3.29 mmol) in acetone (25 ml). The reaction mixture was refluxed for 24 hours under an atmosphere of argon. The resulting mixture was evaporated and the residue was partitioned between 2× ethylacetate and water. The combined organics were washed with water and dried over magnesium sulphate. The orange oil was purified by chromatography on silica gel, eluting with ethyl acetate (0-10%) in hexane to give the title compound as a clear oil (0.661 g, 1.99 mmol). LC/MS: Rt=3.63, [MH]− 331.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[C:2]([I:1])=[N:3]1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Product: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde was prepared from 3-Iodo-1H-indazole-5-carbaldehyde and 1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:25]=[CH:24][C:10]([N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+].C1COCC1>CO>[C:6]([C:7]1[CH:25]=[CH:24][C:10]([N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)#[CH:5]
Reactant: CCCCCCN(CCCCCC)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(N(CCCCCC)CCCCCC)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
4-[(Trimethylsilyl)ethynyl]-N,N-dihexylaniline (1.206 g, 3.37×10−3 mol), K2CO3 (0.558 g, 4.04×10−3 mol), THF (20 ml) and MeOH (20 ml) were added to a 100-ml round-bottom flask. The reaction mixture was stirred at room temperature for 4.5 h under Ar. After the solvent was evaporated, the residue was chromatographed on silica gel with 4:1 hexane:CHCl3 as the eluent. Yield=0.858 g (89% based on 1.206 g of 4-[(trimethylsilyl)ethynyl]-N,N-dihexylaniline). 1H NMR (250 MHz, CDCl3): δ 7.32 (d, 2H, J=8.9 Hz, Ph), 6.52 (d, 2H, J=8.9 Hz, Ph), 3.25 (t, 4H, J=7.7 Hz, —NCH2—), 2.96 (s, 1H, ethynyl-H), 1.46-1.64 (m, 4H, —NCH2CH2—), 1.20-1.42 (m, 12H, —CH2—), 0.90 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 286.253 ((M+H)+) (calcd 286.253).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.[Cl:20][C:21]1[C:22](F)=[N:23][CH:24]=[C:25]([O:27]CCC2OCCO2)[CH:26]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[N:23][C:22]=1[O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: Fc1ncc(OCCC2OCCO2)cc1Cl
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)cn1

Procedure:
Using 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol and 3-chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine, 5-chloro-6-({4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (194 mg) was obtained as a brown solid by the methods as in Example 6-2) and Example 6-3), methods equivalent thereto or combinations of these with usual methods.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[C:16]([N+:20]([O-])=O)[CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:23])=[CH:4][CH:3]=1.C(O)C.C(O)(=O)C.[H][H]>[C].[Pd].CO>[NH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]2[C:11]([N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:14](=[O:15])[C:13]=12)=[O:23]
Reactant: [H][H]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc2c1C(=O)N(CCc1ccc(O)cc1)C2=O
Yield: 24.1 %

Procedure:
10% Palladium-carbon catalyst (water content 50%, 200 mg) was added to a mixed solution of N-[2-(4-hydroxyphenyl)ethyl]-3-nitrophthalimide (1.67 g, 0.0053 mol, 1 eq) in methanol (20 ml)-ethanol (50 ml)-acetic acid (20 ml), and the mixture was stirred for 3 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=50/1) to give 3-amino-N-[2-(4-hydroxyphenyl)ethyl]phthalimide (360 mg, 24.1%) as a colorless solid.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[CH2:10][CH2:11][CH:12]([C:31](N1C(C2C=CC=CC=2)COC1=O)=[O:32])[CH:13]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>COC(C)(C)C.O1CCCC1>[Si:1]([O:8][CH:9]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[CH2:10][CH2:11][CH:12]1[C:31](=[O:32])[N:22]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)[CH:13]1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(Nc2ccc(C#N)cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.2 g of 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2) were dissolved in 380 ml of methyl tert-butylether. 18.6 ml of N,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred at room temperature for 2 h. After the reaction ended, 10 ml of acetic acid were added, the reaction mixture was concentrated under reduced pressure and the residue was purified on silica gel using toluene/ethyl acetate 50/1. This produced 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) of molecular weight 544.75 (C32H37FN2O3Si); MS (ESI): 545.56 (M+H+).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH:44][CH2:45][CH3:46])=[CH:38][CH:37]=1>>[Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:44]([CH2:43][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=1)[CH2:45][CH3:46])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: CCNCCc1ccc(Cl)cc1
Agent: Cl
Product: CCN(CCc1ccc(Cl)cc1)C(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Yield: 43 %

Procedure:
The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and [2-(4-chloro-phenyl)-ethyl]-ethyl-amine hydrochloride (preparation 81), using a similar method to that of preparation 109, as a white solid in 43% yield. 1H NMR (400 MHz, CD3OD) 7.90-6.90 (10H, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, m), 3.70 (1H, m), 3.61 (1H, m), 3.49 (1H, m), 3.10 (1H, m), 3.03-2.58 (6H, m), 1.29-1.26, 1.07-1.01 (9H, 2×m), 0.82 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm; LRMS APCI m/z 639 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16]([O:18][CH3:19])=[O:17])[C:9](=[N:12][N+:13]([O-:15])=[O:14])SC)=[CH:5][N:6]=1.[CH3:20][NH2:21].CO>CO>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]([NH:21][CH3:20])=[N:12][N+:13]([O-:15])=[O:14])=[CH:5][N:6]=1
Reactant: COC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])SC
Reactant: CN
Solvent: CO
Product: CNC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)OC
Yield: 48.5 %

Procedure:
To a solution of N-(2-chloro-5-thiazolylmethyl)-N-methoxycarbonyl-S-methyl-N'-nitroisothiourea (500 mg) in MeOH (5 ml) was added 40% methylamine-methanol solution (120 mg) dropwise below -10° C. and the mixture was stirred at the same temperature. Precipitated crystals were collected by filtration and dried to afford 230 mg of 1-(2-chloro-5-thiazolylmethyl)-1-methoxycarbonyl-3-methyl-2-nitroguanidine (Compound No. 19) as a white crystal. The filtrate was concentrated to leave the residue to which MeOH (3 ml) was added. The product (Compound No. 19, 140 mg) was obtained after drying. The properties, i.e. m.p., NMR and IR, of the product are identical with those of the compound prepared according to Example 3.