Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19](=[O:45])[NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:44])=[C:25]([CH:43]=4)[O:26][C:27](=[O:42])[CH2:28][N:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[CH:14]=3)[C:9]2=[O:46])[CH2:6][CH2:5][C:4](=[O:47])[NH:3]1.[ClH:48]>C(Cl)Cl.CCOCC>[ClH:48].[N:29]1([CH2:28][C:27]([O:26][C:25]2[CH:43]=[C:21]([NH:20][C:19]([NH:18][CH2:17][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:46])[N:8]([CH:7]3[CH2:6][CH2:5][C:4](=[O:47])[NH:3][C:2]3=[O:1])[CH2:16]4)=[O:45])[CH:22]=[CH:23][C:24]=2[CH3:44])=[O:42])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN1CCNCC1
Reaction time: 24 h

Procedure:
To a mixture of tert-butyl 4-(2-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)-2-methylphenoxy)-2-oxoethyl)piperazine-1-carboxylate (0.65 g, 1.0 mmol) in methylene chloride (50 mL) is added 2M HCl in ether (1 mL), and the mixture will be stirred for 24 hrs. The solid precipitate is filtered, rinsed with DCM (10 mL), and dried under vacuum to provide the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[Cl:16])=[O:8].Cl.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:16].[ClH:18].[Cl:16][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8])[NH:15][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: Nc1ccc(C(=O)c2ccccn2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(=O)c4ccccn4)c(Cl)c3)c2cc1OC
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-amino-2-chlorophenyl 2-pyridyl ketone was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(2-pyridylcarbonyl)anilino]-6,7-dimethoxyquinazoline dihydrochloride salt in 45% yield, m.p. 255°-258° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].ClC1C=CC=CC=1.[Br:19]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(=O)c1ccc(C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(CBr)cc1Cl
Temperature: 142.5 °C
Yield: 70 %

Procedure:
A mixture of 1-(2-chloro-4-methylphenyl)ethanone (1.6 g, 9.50 mmol) (preparation 15) and chlorobenzene (60 ml) was prepared at room temperature and N-bromosuccinimide (NBS) (1.86 g, 10.44 mmol) added followed by a catalytic amount of benzoyl peroxide (ca. 1.5 mg, 0.005 mmol), and the resulting mixture was heated to 140-145° C. for 16 h. The mixture was then allowed to cool to room temperature, diluted with toluene (50 ml) and filtered through a celite pad. The pad was washed with toluene (2×50 ml) and the filtrate concentrated under reduced pressure and purified by column chromatography (0-10% EtOAc/Hexanes) to afford 1-(4-(bromomethyl)-2-chlorophenyl)ethanone (1.65 g, 6.65 mmol, 70%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29]([O-:37])(=[Se])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C[O:39]C1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[C:29]([O-:37])(=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Reactant: [O-]C(=[Se])c1ccccc1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: O=C([O-])c1ccccc1

Procedure:
5α-Cholestan-3β-ol-selenobenzoate (278 mg, 0.50 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 0.3 h. 5α-Cholestan-3β-ol-benzoate (229 mg, 93%) was obtained after p.l.c. (petroleum ether-ethyl acetate 9:1). The product obtained was recrystallized from ethyl acetate (198 mg, 80%) m.p. 136°-137° (lit., 136°-137°).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([NH:17][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:15][CH3:16])[CH2:1][CH3:2])=[CH:8][CH:9]=3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Reactant: Nc1ccc2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(CC)CCOc1ccc(CNc2ccc3ncccc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.3 %

Procedure:
To a stirred solution of 1.0 gram (0.0045 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde and 0.65 gram (0.0045 mole) of 6-aminoquinoline (available from Aldrich Chemical Company) in 25 mL of 1,2-dichloroethane (DCE, available from Aldrich Chemical Company) was added 0.3 mL (0.0045 mole) of glacial acetic acid (available from J. T. Baker Inc.) followed by 1.4 grams (0.0068 mole) of sodium triacetoxyborohydride (available from Aldrich Chemical Company). Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, 50 mL of 10% aqueous sodium hydroxide was added dropwise. The resulting solution was extracted with three 25 mL portions of diethyl ether. The extracts were combined, washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.25 grams of a dark brown paste. The dark brown paste was purified by column chromatography on silica gel, yielding 0.13 gram of Compound 15. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[C@:13]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[OH:21])([CH3:18])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[CH2:29][CH3:30]>>[CH2:29]([O:21][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:19][C@:13]1([CH3:18])[C:14]([CH3:17])=[CH:15][C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:30]
Reactant: CCI
Reactant: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CC(O)c1ccccn1
Product: CCOC(C[C@@]1(C)Cc2cnn(-c3ccc(F)cc3)c2C=C1C)c1ccccn1

Procedure:
Using a procedure analogous to Example 35, the diastereomer mixture of the alcohols from Examples 75 and 76 (53 mg, 0.146 mmol) was reacted with iodoethane to give Example 77 as a 1:2 mixture of two diastereomers (20 mg, 35%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(CCl)cc1

Procedure:
4-Chloromethyl-benzoyl chloride (2.82 g, 15 mmol) and cyclopropylamine (1.26 ml, 18 mmol) were reacted in CH2Cl2 (30 ml) and in the presence of Hünig's base (3.1 ml, 18 mmol) for 1 h. A precipitate was formed which was resolubilzed by adding ethyl acetate. The reaction mixture was washed with a 5% KHSO4/10% K2SO4 solution, NaCl sat. solution and dried (Na2SO4). The organic phase was filtered and concentrated under reduced pressure to yield a semi-solid which was triturated in hexanes: solid 3.1 g (95%); 1H NMR (CDCl3) δ 0.60-0.64 (m, 2H), 0.85-0.90 (m, 2H), 2.89-2.92 (m, 1H), 4.60 (s, 2H), 6.20 (br, 1H), 7.44 (d, 2H), 7.71-7.74 (m, 2H); MS: m/e=210.2 (MH+)
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:30][CH:31]1[C:58](=[O:59])[N:33]2[C:34]([C:55]([OH:57])=[O:56])=[C:35]([CH2:38][S:39][C:40]3[N:44]([CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:43]=[N:42][N:41]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:30][CH:31]2[C:58](=[O:59])[N:33]3[C:34]([C:55]([OH:57])=[O:56])=[C:35]([CH2:38][S:39][C:40]4[N:44]([CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])[N:43]=[N:42][N:41]=4)[CH2:36][S:37][C@H:32]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC(C)(C)OC(=O)NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Yield: 83.1 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g), phosphoryl chloride (1.03 g.), 7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (2.6 g.), trimethylsilylacetamide (5.9 g.) and ethyl acetate (50 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.7 g.).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC[C@H]1[C@@H](CC(=O)OC)CC[C@H]1O
Solvent: CO
Product: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)OC

Procedure:
methyl (+)-(1R,2S,3R)-3-hydroxy-2-pentyl-1-cyclopentaneacetate, characterized by a [α]20D superior to +17° (c=1.795 g/ 100 ml, methanol).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C@H:7]1[N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15][C@@:6]21[CH3:24].B(Br)(Br)Br>C(Cl)(Cl)Cl>[C:18]1([CH2:17][CH2:16][N:13]2[C@@H:7]3[N:8]([CH3:12])[C:9]4[C:5]([C@:6]3([CH3:24])[CH2:15][CH2:14]2)=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2c(c1)[C@]1(C)CCN(CCc3ccccc3)[C@@H]1N2C
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: CN1c2ccc(O)cc2[C@]2(C)CCN(CCc3ccccc3)[C@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution under nitrogen of 3.22 g of (3aS-cis)-1,2,3,3a,8,8a-hexahydro-5-methoxy-1-(2-phenylethyl)-3a,8-dimethylpyrrolo[2,3-b]indole in 50 ml of degassed chloroform is added dropwise at 0° C. a solution of 10.1 g of boron tribromide in 50 ml of degassed chloroform. The mixture is stirred for about 3 days at room temperature, cooled to 0° C. and cautiously quenched by the dropwise addition of water. The mixture is stirred vigorously for 0.5 hour, and a sufficient volume of saturated aqueous sodium bicarbonate solution is added to make the system just basic to a pH paper. The organic phase is separated, dried over anhydrous sodium sulfate and concentrated. The residue is Kugelrohr distilled at 0.1 mm Hg at an oven temperature of 160°-200° to provide pure (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1-(2-phenylethyl)-3a,8-dimethylpyrrolo[2,3-b]indol-5-ol.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.C1(S([N:20]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[C:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=3)=[CH:21]2)(=O)=O)C=CC=CC=1>>[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[C:22]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:1][CH:2]3[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]3)[N:30]=2)=[CH:21]1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: CC(=O)N1CCC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1
Yield: 12.1 %

Procedure:
Using the procedure of example 1, 1-(4-aminopiperidin-1-yl)ethanone (350 mg) was reacted with compound 1f (300 mg) to provide compound 64 (33 mg, 12%). 1H NMR (300 MHz, CDCl3) δ 11.45 (s, 1 H), 8.75 (d, 1 H), 8.40 (d, 1 H), 8.20 (d, 1 H), 8.12 (s, 1 H), 8.00 (s, 1 H), 7.20 (m, 1H), 6.90 (d, 1 H), 5.40 (m, 1 H) (rotamer), 4.55 (m, 1 H), 4.20-3.70 (m, 2 H), 3.40-2.70 (m, 2 H), 2.20 (m, 2 H), 2.15 (s, 3 H), 1.50 (m, 2H). MS (ESI) m/z: 337 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([OH:28])=O)[CH:7]=1.Cl.[NH2:42][C@@H:43]([C:45]([NH2:47])=[O:46])[CH3:44]>>[NH2:47][C:45](=[O:46])[C@H:43]([NH:42][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH3:44]
Reactant: C[C@@H](N)C(N)=O
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Agent: Cl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-alaninamide hydrochloride.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11]2
Reactant: NCCCc1ccccc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cccc2CN1CCCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 3-phenyl-propylamine (0.071 mL, 0.5 mmol), and K2CO3 (0.138 g, 1 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.054 g, 48%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.72 (t, 2H), 3.66 (t, 2H), 4.25 (s, 2H), 7.14-7.42 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[N:45][C:46]([CH2:49][CH3:50])=[CH:47][CH:48]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[N:44]=[N:45][C:46]([CH2:49][CH3:50])=[CH:47][CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: CCc1ccc(-c2cc(C)c(Cl)c(C)c2)nn1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: CCc1ccc(-c2cc(C)c(-c3ccc(F)c4c3CC[C@H]4Oc3ccc4c(c3)OC[C@H]4CC(=O)OC)c(C)c2)nn1

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-chloro-3,5-dimethyl-phenyl)-6-ethyl-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.14 min; Mass spectrum (ESI+): m/z=553 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[O:10]=[C:11]1[CH2:16][C:15](=O)[CH2:14][CH2:13][NH:12]1>C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:15]1[CH2:14][CH2:13][NH:12][C:11](=[O:10])[CH:16]=1
Reactant: O=C1CCNC(=O)C1
Reactant: Nc1cc(F)ccc1F
Solvent: CCO
Product: O=C1C=C(Nc2cc(F)ccc2F)CCN1
Yield: 20.5 %

Procedure:
A mixture of 2,5-difluoroaniline (6.45 g) and 2,4-dioxopiperidine (5.66 g) was heated under nitrogen for 6 h. The reaction mixture was then dissolved in ethanol (50 ml), adsorbed onto silica, and purified by FCC eluting with System A (150:8:1) to give the title compound (2.3 g), m.p. 252°-255°.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[F:13][C:14]([F:52])([F:51])[C:15]1[CH:16]=[C:17]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:18][N:19]([C:42]#[N:43])[CH:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]2[C:33]([CH3:41])=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:21]1=2.Cl>C1(C)C=CC=CC=1.ClCCl>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:17]([CH:16]=[C:15]([C:14]([F:52])([F:51])[F:13])[CH:46]=1)[CH2:18][N:19]([C:42]1[NH:43][N:3]=[N:2][N:1]=1)[CH:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]2[C:33]([CH3:41])=[C:34]([C:37]([F:38])([F:39])[F:40])[CH:35]=[CH:36][C:21]1=2
Reactant: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Add sodium azide (42 mg, 0.64 mmol) and triethylamine hydrochloride (88 mg, 0.64 mmol) to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (124 mg, 0.21 mmol) in toluene (2 mL). Stir the mixture at 110° C. overnight. Cool down the mixture to room temperature, add 1N HCl (5 mL) and dichloromethane. Separate the layers, dry the organic phase over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure to provide 117 mg (89%) of the title compound. MS (ES−): 623 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CC1C=CN=CC=1.F[O:17][C:18](=O)[CH3:19]>>[C:18]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)(=[O:17])[CH3:19]
Reactant: CC(=O)OF
Reactant: Cc1ccnc(O)c1
Solvent: Cc1ccncc1
Product: CC(=O)Oc1cc(C)ccn1

Procedure:
As a process for the preparation of 2-hydroxy-4-methylpyridine, a process whereby [iv] 4-methylpyridine is reacted with acetyl hypofluorite at −10° C. to obtain a 2-acetoxy-4-methylpyridine, and thereafter the 2-acetoxy-4-methylpyridine is hydrolyzed to obtain 4-methyl-2-pyridone is reported [Journal of the American Chemical Society, 109, 3789-3790, (1987): Non-Patent Reference 2].
Reaction SMILES: [CH3:1][N:2]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54]([F:57])([F:56])[F:55])[C:3]([N:5]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:22]=[N:21][N:20]=2)=[CH:9][CH:8]=1)=[O:4].C(O)(=O)C.CO>C(Cl)Cl>[CH3:1][N:2]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54]([F:57])([F:56])[F:55])[C:3]([N:5]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:9][CH:8]=1)=[O:4]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Yield: 31 %

Procedure:
By the procedure of Example 8, Step D, 1-methyl-3-pentyl-1-[2-(trifluoromethyl)phenyl]-3-[[2'(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]urea (from Step A) was deprotected with aqueous acetic acid. The residual oil was flash chromatographed on silica gel (elution with 3% and then 5% MeOH in CH2Cl2) to give a 31% yield of the title compound as a stiff foam, homogeneous by TLC (95:5 CH2Cl2 -MeOH); FAB-MS m/e 523 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[N:5]=[C:4]([CH3:11])[N:3]=1.C(N(C(C)C)CC)(C)C.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CC(N(C)C)=O>[Cl:10][C:6]1[N:5]=[C:4]([CH3:11])[N:3]=[C:2]([N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:25][CH2:26]2)[C:7]=1[O:8][CH3:9]
Reactant: c1cnc2nc(C3CCNCC3)ccc2c1
Reactant: COc1c(Cl)nc(C)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1c(Cl)nc(C)nc1N1CCC(c2ccc3cccnc3n2)CC1
Temperature: 120 °C
Yield: 50.5 %

Procedure:
30 ml of dimethylacetamide, 0.9 g (4.66 mmoles) 4,6-dichloro-2-methyl -5-methoxy-pyrimidine and 3 ml of diisopropylethylamine are added into a single-necked flask containing 1.1 g (5.2 mmoles) of 2-piperidin-4-yl-[1,8]naphthyridine. This mixture is heated at 120° C. for 4 hours then concentrated to dryness under reduced pressure (2 kPa). The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The collected organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silica gel eluting with a gradient of heptane-ethyl acetate of 100-0 to 0-100. 870 mg of expected product is obtained in the form of a yellow solid.