Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:30])/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.Cl>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:30])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 45 %

Procedure:
A 2.5 ml portion of 10 N aqueous sodium hydroxide was added to 2.3 g of 4-[[4-[(3-bromophenyl) amino]-6-quinazolinyl]amino]-4-oxo-(E)-2-butenoic acid ethyl ester (Example 5) in 25 ml of ethanol. After stirring for an hour, 2.1 ml of concentrated hydrochloric acid was added, and the reaction was stirred an additional 2 hours. The resulting solid was recrystallized from n-butanol to give 0.97 g of 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)-2-butenoic acid: mass spectrum (m/e): M+H 413.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[Cl:13][C:14]1[N:19]=[C:18]2[S:20][N:21]=[C:22]([CH3:23])[C:17]2=[CH:16][CH:15]=1.[Br:24]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:23][C:22]1[C:17]2[C:18](=[N:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[S:20][N:21]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1nsc2nc(Cl)ccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(CBr)nsc2n1
Temperature: 80 °C

Procedure:
AIBN (1.35 mmol) was added to a solution of 6-chloro-3-methylisothiazolo[5,4-b]pyridine (13.5 mmol) and N-bromosuccinamide (27.1 mmol) in carbon tetrachloride (25 mL). The reaction mixture was heated at 80° C. for 6 h, allowed to cool to rt, and the precipitated solids were removed by filtration. The filtrate was concentrated to provide crude 3-(bromomethyl)-6-chloroisothiazolo[5,4-b]pyridine as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]=[CH:7][NH:6][C:5]2=[O:13].[H-].[Na+].[CH3:16][SH:17]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:17][CH3:16])[N:8]=[CH:7][NH:6][C:5]2=[O:13]
Reactant: CS
Reactant: O=c1[nH]cnc2cc(Cl)c(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2nc[nH]c(=O)c2cc1Cl
Temperature: 120 °C

Procedure:
Under a nitrogen atmosphere in a flame dried flask equipped with a magnetic stirrer and a reflux condenser, a mixture of 1.00 g (0.00465 mol) of 6,7-dichloroquinazolin-4(3H)-one and 18 ml of dimethylformamide was treated at room temperature with 0.56 g (0.012 mol) of 50% sodium hydride in mineral oil. Foaming began immediately and most of the solids dissolved. When the foaming had subsided, 1.8 ml (0.0176 mol) of 47% methyl mercaptan in dimethyl formamide was added to the stirred mixture. The mixture was heated at 120° C. for six hours. When the reaction mixture was again at room temperature, a small amount of insoluble matter was filtered, and was rinsed with a few ml of dimethylformamide. The filtrate was washed three times with 10 ml portions of hexane. The filtrate was then poured into 300 ml of ice and water. By the addition of 2N hydrochloric acid, the aqueous solution was adjusted to pH 2. There formed a fine colorless precipitate which was filtered, washed with water, air dried and pressed on a clay plate to furnish the title compound: yield 0.97 g (92%); m.p. 292°-295° C. (dec.); mass spectrum m/e 226 (parent peak and molecular ion with expected isotope pattern), 193 (-33) among others; 1H-NMR(DMSO-d6) 2.6 ppm (singlet, 3H, SCH3), 7.45 (singlet, 1H, aromatic H), 8.0 (singlet, 1H, aromatic H), 8.15 (singlet, 1H, N=CH-N).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]2[CH3:26])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:29][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]2[CH3:26])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CCl
Temperature: 0 °C

Procedure:
4 g (10 mmol) of 2-hydroxymethyl-3-methyl-4-{4-[2-(2-methyl-5-nitroimidazol-1-yl)ethylthio]butylthio}-pyridine are dissolved in 40 ml of dichloromethane. 1.56 g (13.11 mmol) of thionyl chloride in 5 ml of dichloromethane are added dropwise with ice-cooling. The mixture is stirred at 0C for 2 h. It is then added to 250 ml of ice-water and neutralized with saturated sodium hydrogen carbonate solution. The dichloromethane phase is separated off and the aqueous phase is extracted again with dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated. The title compound is obtained as a yellow oil which is reacted without further purification. Yield 4.15 g (100% of theory).
Reaction SMILES: [CH:1]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[CH:1]1([C:6]2[N:7]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]4/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=5[O:24][CH2:25][C:19]=4[CH:18]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2[nH]c(C3CCCC3)nc2c1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 95.3 %

Procedure:
Using 2-cyclopentyl-1H-benzo[d]imidazole (62 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (148 mg, 95%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([CH3:11])=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([CH3:11])=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(C)n(-c2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(C)n1-c1ccccc1
Temperature: 70 °C
Yield: 92.5 %

Procedure:
Part D: To a magnetically stirred solution of methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (8.0 gram, 0.035 mol) in THF (100 ml) was added a solution of LiOH (1.68 gram) in water (100 ml). The resulting mixture was heated at 70° C. for 16 hours, allowed to attain room temperature and acidified with 2 molar equivalents of a 1N HCl solution. The formed precipitate was collected to give crude 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (7.0 gram, 93% yield). 1H-NMR (400 MHz, DMSO-d6): 2.31 (s, 3H), 2.43 (s, 3H), 7.56-7.61 (m, 2H), 7.66-7.71 (m, 3H).
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:29][C:30]1[CH:31]=[C:32]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[N:44][C:45]=3[NH2:47])[NH:40][N:39]=2)[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=1>>[NH2:47][C:45]1[N:44]=[CH:43][N:42]=[C:41]2[N:40]([CH:2]([C:4]3[O:5][C:6](=[O:28])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)[CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:39]=[C:38]([C:32]3[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=[C:30]([F:29])[CH:31]=3)[C:46]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(CN2CCN(C)CC2)c1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3cccc(CN4CCN(C)CC4)c3)c3ncnc(N)c23)c1
Yield: 34.2 %

Procedure:
The title compound was made in a similar way as that of example 134, step a, from 3-(1-hydroxyethyl)-4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (Intermediate B49, 350 mg, 0.925 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 264 mg, 1.017 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (196 mg, 0.316 mmol, 34.2% yield) as a brown solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)(C)C)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide (Intermediate 15, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([CH3:22])[CH2:5][N:6]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([CH3:22])[CH2:5][N:6]([C:12]1[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)CN(c1nc(Cl)ncc1N)C1CCCC1
Yield: 94.6 %

Procedure:
A mixture of 40.64 g (0.119 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (IV-1) in 1500 mL of ethyl acetate and 14 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration under reduced pressure gave 35.2 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (V-1), which also contained a small amount of (rac-)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one. This material was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.B(F)(F)F>O1CCCC1>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Temperature: 20 °C

Procedure:
A mixture of 22 g (0.10 mole) of 2,6-di(tertiary-butyl)-p-benzoquinone, 13.7 g (0.10 mole) of 4-aminobenzoic acid, 175 ml of tetrahydrofuran and 1 ml of boron trifluoride: diethyl ether complex was heated on a steam bath for 1.25 hours. The mixture was allowed to cool to about 20° C over 16 hours under a nitrogen atmosphere. Evaporation provided a solid which was washed with hexane and recrystallized from ethanol to provide orange solid 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one, m.p. 305°-309° C. Analysis: Calculated for C21H25NO3 : % C, 74.3; % H, 7.4; % N, 4.1; Found: % C, 74.2; % H, 7.4; % N, 4.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].S(O)(O)(=O)=O.[CH3:23][O:24][C:25](=[NH:27])[NH2:26].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:27][C:25]([O:24][CH3:23])=[N:26][C:15]([CH3:16])=[C:10]2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C(=Cc1ccc(F)c(F)c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)c(F)c1
Temperature: 70 °C
Yield: 35.2 %

Procedure:
A mixture of methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate (8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4 g, 55 mmol), and NaHCO3 (12.3 g, 0.146 mol) in DMF (30 mL) was stirred and heated at 70° C. for 16 hours. The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5×300 mL), brine (300 mL), and dried (MgSO4). Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through 20% EtOAc in hexane as the gradient eluent, to leave the product as an oil (3.82 g, 30.2%); 1H-NMR (CDCl3): δ2.32,2.39 (2 s, 3 H), 3.58, 3.64 (2 s, 3 H), 3.72, 3.85 (2 s, 3 H), 5.55 (s, 1H), 6.13-7.8 (m, 4 H).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])(O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC1(O)CCN(c2nnc3ccc(F)cn23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Yield: 96.3 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (550 mg, 1.81 mmol) was added to a solution of Intermediate 79c (150 mg, 0.60 mmol) and Et3N (242 mg, 2.40 mmol) in a DCM (5 mL) and the mixture stirred at reflux for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (2×), brine, dried (MgSO4), and then concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (235 mg, 96%). 1H NMR (400 MHz, CDCl3): 1.00-1.20 (21H, m), 1.40 (3H, s), 1.76-1.93 (4H, m), 3.18-3.29 (2H, m), 3.44-3.58 (2H, m), 7.03-7.12 (1H, m), 7.58-7.69 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.Cl[C:21]([F:27])([F:26])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH:21]([F:27])[F:26])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Reactant: COC(=O)C(F)(F)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (1.8 g) obtained in Reference Example 132-(1) was dissolved in dimethylformamide (15 ml), and added thereto were methyl 2-chloro-2,2-difluoroacetate (1.63 ml) and potassium carbonate (2.28 g), and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction mixture was acidified with 2N aqueous HCl solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(6-difluoromethoxybenzo[b]thiophen-2-yl methyl) benzene (695 mg) as a colorless solid. GC-Mass m/Z 402/404 (M+).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([C:15](=[O:19])[N:16]([OH:18])[CH3:17])[CH:7]=1)[CH:2]=[CH2:3].[CH2:21](Br)[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([C:15](=[O:19])[N:16]([O:18][CH2:23][CH:22]=[CH2:21])[CH3:17])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCOC(=O)c1cc(C(=O)N(C)O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(C(=O)N(C)OCC=C)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A mixture of (8(a)) (0.60 g), allyl bromide (0.28 g), potassium carbonate (0.59 g) and DMF (20 ml) was stirred for 3 hours at ambient temperature under an argon atmosphere. The dimethyl formamide was then evaporated under reduced pressure and the residue dissolved in ethyl acetate (50 ml) and water (50 ml). The organic phase was separated, washed with brine (50 ml), dried over magnesium sulphate and evaporated under reduced pressure to dryness to give 3-(N-methyl-allyloxycarbamoyl)-5-nitro-benzoic acid allyl ester (8(b)) as a yellow oil (0.571 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1>>[CH:1]1([CH2:7][CH2:8][O:9][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCC1CCCCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OCCC2CCCCC2)cc1

Procedure:
2-Cyclohexylethanol 15-1 (3.2 g, 25 mmol) and ethyl 4-hydroxybenzoate 15-2 (4.15 g, 25 mmol) were reacted as in Example 14. The product 15-3 was obtained as a waxy solid.
Reaction SMILES: CCOCC.[Na].Cl[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(Cl)C(=O)O
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: CCOCC
Product: CC(OCc1ccccc1)C(=O)O
Temperature: 150 °C

Procedure:
An alternate method for the preparation of ether compounds corresponding to Formula I (R=alkyl, phenylalkyl) follows. Sodium metal (about 12 g) was added cautiously to a stirred cold (ice bath) portion (250 mL) of benzyl alcohol. After most of the sodium metal had dissolved, the reaction was heated to 150° C. 2-Chloropropionic acid (27.2 g, 0.25 mole) was added dropwise in 35 mL of benzyl alcohol and the resulting mixture heated on additional 3 hours. Concentration in vacuo gave crude 2-benzyloxypropionic acid which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10](=O)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)CCC(=O)C2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc2c(c1)CCC(N1CCCC1)=C2
Yield: 100.9 %

Procedure:
To a stirred solution of 6-t-butyl-2-tetralone (5.74 g; 28.37 mmol) in 100 ml of toluene was added 1.5 equiv. of pyrrolidine (3.56 ml; 42.56 mmol). A 100 mg portion of p-toluenesulfonic acid was added and the mixture was refluxed. The water eliminated during the reaction was collected by a Dean Stark trap. After a reflux time of 3.5 hours, concentration of the volatiles under vacuum afforded 7.31 g of the subtitle compound as a purple solid.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:18][CH2:17][C:15]1[Se:16][C:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CC(C)[Si](Oc1ccc(-c2ccc(CO)[se]2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccc(O)cc2)[se]1
Reaction time: 0.5 h

Procedure:
8.7 g (21.4 mmol) of [5-(4-triisopropylsilanyloxyphenyl)selenophen-2-yl]-methanol are initially introduced in 200 ml of THF, and 50 ml of TBAF (50 mmol, 1 M soln. in THF) are added with ice-cooling. After 30 min at this temperature, the mixture is added to water and extracted with MTBE. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is recrystallised from ethyl acetate. 4-(5-Hydroxymethylselenophen-2-yl)phenol is obtained as a beige solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)[CH2:3][C:4]#[N:5]>CCOC(C)=O.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]([CH:2]([OH:1])[CH2:3][C:4]#[N:5])[CH:11]=[CH:10][CH:9]=1
Reactant: N#CCC(O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCC(O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 3-hydroxy-3-(3-nitrophenyl)propanenitrile (11) (400 mg, 2.1 mmol) and Pd/C (20 mg, 10%) in EtOAc (15 ml) was degassed vacuum/hydrogen and then stirred at room temperature under H2 (balloon) for 15 hours. The mixture was filtered to remove the Pd/C and then concentrated under reduced pressure to give 3-(3-aminophenyl)-3-hydroxypropanenitrile (12) as while solid. Yield (390 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 7.15 (t, J=8.0 Hz, 1H), 6.70-6.74 (m, 2H), 6.63-6.65 (m, 1H), 4.92 (t, J=6.0 Hz, 1H), 2.72 (d, J=6.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]12[CH2:6][C:4]([C:7]([OH:9])=O)([CH2:5]1)[CH2:3]2.C[Li].[Cl-].[NH4+].[C:14](OCC)(=O)C>C1COCC1>[NH2:1][C:2]12[CH2:3][C:4]([C:7](=[O:9])[CH3:14])([CH2:5]1)[CH2:6]2
Reactant: CCOC(C)=O
Reactant: NC12CC(C(=O)O)(C1)C2
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C12CC(N)(C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid (1 mmol) in anhydrous THF (2 mL) at 0° C. under nitrogen is added a methyllithium (1.4 M in diethyl ether, 4 mmol) in a dropwise manner. After addition, the reaction mixture is slowly allowed to warm to room temperature (r.t.), stirred overnight, and treated with aqueous saturated ammonium chloride solution (4 mL). Ethyl acetate (2 mL) is added and organic layer are separated. The aqueous layer is extracted with ethyl acetate (3×1 mL). The combined organic layers are dried (Mg2SO4) and concentrated. The residue is purified by a flash chromatography on silica gel (EtOAc/hexanes) to give 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone.