Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6])[N:20]=1
Reactant: NC(N)=S
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)O)cs1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 18.6 %

Procedure:
To a solution of 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (20 g) in tetrahydrofuran (50 ml) was added a solution of thiourea (3.9 g) and sodium acetate (4.2 g) in water (50 ml), and the mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to half of the original volume, which was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate and then washed with ethyl acetate. After the aqueous solution was further adjusted to pH 2.0 with 10% hydrochloric acid, the water was removed by decantation. The residual substance was dissolved in tetrahydrofuran (200 ml), followed by drying over magnesium sulfate. Removal of the solvent gave an oil, which was triturated with diisopropyl ether to give 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetic acid (syn isomer) (3.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:9])[CH3:1])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CN(C)CCCCCN
Product: CN(C)CCCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 5-dimethylamino-pentylamine (reference example 93a) and and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 496 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15](=[NH:17])[NH2:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[C:15]([NH2:16])[NH:17][C:15]=1[NH2:16])=[O:18])[CH3:11]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1F
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1F
Yield: 49 %

Procedure:
Upon boiling a solution of 6.2 g 2-fluorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 1 hour, 2,6-diamino-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 128° - 130°C (ethanol) is obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][C:15]4[NH:20][N:21]=[C:22]([C:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=5)[C:14]=4[C:13]=3[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36]>ClCCl.O1CCOCC1>[Cl-:36].[C:1]1([NH:7][C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][C:15]4[NH:20][N:21]=[C:22]([C:23]5[CH2:28][CH2:27][NH2+:26][CH2:25][CH:24]=5)[C:14]=4[C:13]=3[CH2:12][CH2:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2n[nH]c3ncc4c(c23)CCN(C(=O)Nc2ccccc2)C4)CC1
Reactant: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCc2c(cnc3[nH]nc(C4=CC[NH2+]CC4)c23)C1
Product: [Cl-]

Procedure:
To a solution of tert-butyl 4-(7-(phenylcarbamoyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.06 g, 0.12 mmol) was dissolved in dichloromethane (5 mL) and 4M HCl in 1,4-dioxane (0.5 mL) was added and stirred till complete as observed by LCMS. The reaction mixture was then evaporated in vacuo. (0.04 g, 80%). M.p.=230-231° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.35 (br s, 2H), 8.78 (s, 1H), 8.36 (s, 1H), 7.52-7.49 (d, J=7.4 Hz, 2H), 7.24-7.22 (t, J=7.8 Hz, 2H), 6.96-6.92 (t, J=7.4 Hz, 1H), 6.05 (s, 1H), 4.82 (s, 2H), 3.78-3.74 (m, 5H), 3.36-3.35 (br s, 2H), 3.18 (t, J=6 Hz, 2H), 2.77 (br s, 2H); LCMS [M+H]: 375.
Reaction SMILES: COC(C1CCCN1C(C1N2C(COCC2)=C(C(=O)N[C@@H](C2C=CC=CC=2)CC)C=1)=O)=O.[CH:33]([O:36][C:37]([CH:39]1[CH2:43]C[CH2:41][N:40]1[C:44]([C:46]1[N:54]2[C:49]([CH2:50][O:51][CH2:52][CH2:53]2)=[C:48]([C:55](=[O:66])[NH:56][C@@H:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:58][CH3:59])[CH:47]=1)=[O:45])=[O:38])(C)[CH3:34].C(O)(C)C>C(O)C>[CH2:33]([O:36][C:37](=[O:38])[C@@H:39]([N:40]([CH3:41])[C:44]([C:46]1[N:54]2[C:49]([CH2:50][O:51][CH2:52][CH2:53]2)=[C:48]([C:55](=[O:66])[NH:56][C@@H:57]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH2:58][CH3:59])[CH:47]=1)=[O:45])[CH3:43])[CH3:34]
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCCC2C(=O)OC(C)C)n2c1COCC2)c1ccccc1
Agent: CC[C@@H](NC(=O)c1cc(C(=O)N2CCCC2C(=O)OC)n2c1COCC2)c1ccccc1
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)[C@H](C)N(C)C(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)c2n1CCOC2

Procedure:
The compound was obtained from comp. no. 16m as starting compound in analogy to the synthesis of comp. no. 16n. Isopropanol was replaced by ethanol to form the ester. LC/MS (method 4): Rt=1.24 min; m/z=454.27 (M+H+)
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>CCOCC>[Br:1][CH:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:12][CH2:13][CH2:14]1)=[O:21]
Reactant: COCCCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: BrBr
Solvent: CCOCC
Product: COCCC(Br)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.35 ml) was added dropwise over 20 minutes at ambient temperature to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-one (2 g) in ether (40 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 1 hour then it was washed with water (30 ml), saturated aqueous sodium hydrogen carbonate solution (2×30 ml) and water (30 ml), dried (MgSO4), and the solvent removed in vacuo to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-one as an oil which was used without purification.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:69])/[C:31](=[N:57]\[O:58][C:59]([CH3:68])([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH3:60])/[C:32]3[N:33]=[C:34]([NH:37][C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:35][CH:36]=3)[C:27](=[O:70])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:71].[Na+]>CC(C)=O.C(OCC)(=O)C>[I:71][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:69])/[C:31](=[N:57]\[O:58][C:59]([CH3:68])([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH3:60])/[C:32]3[N:33]=[C:34]([NH:37][C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:35][CH:36]=3)[C:27](=[O:70])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A mixture of diphenylmethyl 3-[(Z)-3-chloro-1-propen-1-yl]-7-[(Z)-2-(1-methyl-1-t-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxy-late (IXa) (488 mg, 0.5 mmol) and sodium iodide (225 mg, 1.5 mmol) in acetone (5 ml) was stirred at room temperature for 2 hours and diluted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate, dried over anhydrous MgSO4 and concentrated to afford 546 mg (yield, quantitative) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[I:17]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:17])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: Clc1ccc2nc(-c3ccccc3)cn2n1
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1ccc2nc(-c3ccccc3)c(I)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution, cooled to 0° C., of 10.4 g (45.4 mmol) of 6-chloro-2-phenylimidazo[1,2-b]pyridazine (CAS No.: 1844-53-7) in 500 mL of chloroform is rapidly added dropwise a solution of 11.1 g (68.1 mmol) of iodine monochloride in 100 mL of chloroform. After cooling to room temperature and stirring for 1 hour, the mixture is treated with aqueous 5% sodium thiosulfate solution. The product is extracted with dichloromethane and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is triturated in 150 ml of acetonitrile containing a few mL of isopropyl alcohol and the solid is isolated after filtration. 15 g of a yellow powder are isolated after drying under vacuum.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[N:5]1)(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][Br:14])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(C)c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)n1nc(CBr)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 320 g (1.84 mol) of 1-acetyl-3-methylindazole, 327 g (1.84 mol) of N-bromosuccinimide and 3 liters of carbon tetrachloride solution containing 0.2 g of benzoyl peroxide was refluxed over a 2-hour period as the mixture was irradiated with light. After cooling to room temperature, 0.2 g of benzoyl peroxide was further added, and the reaction mixture was refluxed for additional three hours. After conclusion of the refluxing step, the reaction mixture was cooled to 20° C. to precipitate succinimide. The precipitate of succinimide was filtered out, and the filtrate was concentrated under reduced pressure. To the residue was added 1.2 liters of n-hexane to precipitate crystals. The crystals was filtered off, and washed with n-hexane. Thus, 275 g of crude bromomethyl body was obtained. It was found from measurements of thin-layer chromatograph and NMR spectrum that the crude bromomethyl body was contaminated by about 17% of dibromomethyl body.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])[N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: C1CCNC1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCCC1

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(pyrrolidin-1-yl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and pyrrolidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[CH:29]=[CH:28][C:23]([CH2:24][N:25]=[C:26]=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.ClCCl>[C:16]([C:20]1[CH:29]=[CH:28][C:23]([CH2:24][NH:25][C:26](=[O:27])[NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (1.13 g) prepared in step 3 of Example 1 was dissolved in DMF (6 mL) and diluted with dichloromethane (35 mL). To the solution were added 4-t-butylbenzylisocyanate (1.09 g) and TEA (1.2 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with ethylacetate (20 mL) and washed with water and saturated NaCl aqueous solution. The resulting solution was dried over anhydride MgSO4 and the remaining liquid was concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane/ethyl acetate=312) to yield title compound (1.23 g, 53%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].Cl.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[OH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:15][CH2:16]1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a stirred solution of 3-nitrobenzoyl chloride (10.0 g, 53.9 mmol) in DCM (10 ml) was added piperidin-4-one hydrochloride (10.96 g, 81.0 mmol) and triethylamine (22.53 ml, 162.0 mmol). The reaction mixture was stirred at room temperature for 30 min and evaporated to dryness. The crude material was treated with diethyl ether, solid obtained was filtered and dried under vacuum to give the title compound (9.0 gm).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4](I)[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([O:21][CH3:22])[CH:13]=1>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=2[O:21][CH3:22])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnc(Cl)cc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine (prepared according to WO2006013050) and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Off-white solid (81%). MS (ESI): m/z=267.07 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10]C)=O)[CH:4]=1.C[O-].[Na+].[CH3:15][NH:16][CH3:17]>CO>[OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([N:16]([CH3:17])[CH3:15])=[O:10])[CH:4]=1
Reactant: COC(=O)c1csc(CO)c1
Reactant: CNC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)c1csc(CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 5-(hydroxymethyl)-3-thiophenecarboxylate (3 g), sodium methoxide (0.2 g) and excess anhydrous dimethylamine in dry methanol (20 ml) was stirred for 24 h at ambient temperature. The solvent was removed in vacuo, water was added and the product was extracted with ethyl acetate. The organic extract was evaporated to leave an oily residue which was chromatographed on silica with ethyl acetate-light petroleum 40°-60°; (1:1) to give the title compound (1.3 g). I.R. (CHBr3) OH 3,595 cm-1 ; C=O 1,620 cm-1
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:6]=12.CO.C1COCC1.[Cl-].[NH4+]>CCOC(C)=O.[Zn]>[NH2:22][C:20]1[CH:19]=[CH:18][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:11][CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:6]=23)=[C:2]([F:1])[CH:21]=1
Reactant: COC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of methyl 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (230 mg, 0.69 mmol) in a mixed solvent (10 mL of MeOH and 10 mL of THF) were added ammonium chloride (185 mg, 3.45 mmol) and zinc dust (226 mg, 3.45 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (50 ml), and filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give the desired product (207 mg, 100%) as a yellow solid. MS(ESI+) m/z 302.2 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.CO>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)c1cc(Br)ccn1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Reaction time: 0.42 h
Yield: 18.8 %

Procedure:
n-Butyllithium (0.254 mL, 0.63 mmol) was dropwise added to 4-bromo-2-(difluoromethyl)pyridine (120 mg, 0.58 mmol) in anhydrous THF (5.00 mL) at −78° C. under argon atmosphere. The reaction mixture was stirred for 25 min. N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (235 mg, 0.58 mmol) in anhydrous THF (5.00 mL) was dropwise added. The reaction mixture was stirred for 2 h, then methanol (5 mL) was added and the temperature was allowed to reach room temperature. The reaction mixture was partitioned between aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (47.1 mg, 18%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]=[CH:43][N:42]([CH3:45])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]=[CH:43][N:42]([CH3:45])[N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncn(C)n4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncn(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1-methyl-1H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.8 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.46 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 0.5 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:3), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1-methyl-1H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 126) (678.9 mg) as yellow crystals.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]([O:27][C:28](=[O:43])[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][C:37]([NH2:39])=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:40][CH2:41][CH3:42])([CH3:26])([CH3:25])[CH3:24]>ClCCCl.O>[C:23]([O:27][C:28](=[O:43])[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][C:37]([NH:39][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:40][CH2:41][CH3:42])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCc1nc2cc(N)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (1.8 g, 8.4 mmol) was added to a solution of benzaldehyde (0.68 mL, 6.5 mmol) and (5-amino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (1.8 g, 6.5 mmol) in DCE (15 mL), and stirred overnight at room temperature. The reaction solution was diluted with H2O. The organic solution was washed with brine, dried over MgSO4, and concentrated to afford the subtitle compound that was used without further purification. MS calculated for C23H29N3O2+H: 380, observed: 380.