Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([OH:21])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=CC=CC=1.CO[CH:31](OC)[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=1[O:40][CH3:41].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:21][CH:31]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])[N:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzoyl-β-phenyl isoserine methyl ester (3A, 0.5 g, 1.67 mM) is dissolved in dry THF (10 mL) and benzene (10 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (4, 0.420 g, 1.98 mM) and pyridinium p-toluenesulfonate (12 mg) and the solution warmed to reflux. After 30 minutes the reaction is cooled to RT and allowed to stand overnight. It is then again warmed to slowly distill off 1/2 of the solvent over 1 hr. TLC shows the reaction to be finished at this point. The reaction is concentrated in vacuo and the residue chromatographed over 50 g silica gel packed in (5-95) methanol-toluene. The column is eluted with methanol-toluene (5-95). Fractions of 12 mL are collected. The product elutes as a mixture. Thus, fractions containing both 5Aa & 5Ab are recombined and evaporated. The residue (0.90 g) is rechromatographed over silica gel (100 g) The column is eluted with ethyl acetate-toluene (500 mL of 15-85 and 500 mL of 20-80). Fractions of 20 mL are collected and analyzed by TLC. The fractions containing each 5Aa & 5Ab are combined and evaporated under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCOCC1
Agent: [Pt]
Solvent: CC#N
Solvent: CC(C)O
Product: Nc1cnc2cc(Br)ccc2c1NCC1CCOCC1
Reaction time: 2 h

Procedure:
7-Bromo-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (20 g, 55 mmol) was dissolved in a mixture of acetonitrile (500 mL) and isopropyl alcohol (50 mL) and the solution was placed in a pressure bottle. Platinum on carbon (5%, 2 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 2 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give 7-bromo-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine which was carried forward without further purification assuming quantitative yield.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
Trichloromethyl chloroformate (13.0 g, 65.8 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol 16 (12.4 g of 65%, 29.9 mmol) and triethylamine (12.7 g, 125.5 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 15 h, allowing to warm to room temperature. The mixture was then washed with HCl (3×200 ml) and water (2×200 ml), and dried over MgSO4. Concentration gave a crude product, which was washed with diethyl ether to afford the title compound 17 (7.9 g, 90%) as a white solid. m.p. 212–214° C. [α]D25=−286.1° (c, 4.32 in CHCl3). δH 0.85 (3H, d, J=6.6 Hz, CH3), 0.91 (3H, d, J=6.6 Hz, CH3), 0.96–1.08 (2H, m, CH2), 1.53–1.73 (1H, m, CH—Me2), 4.57 (1H, dd, J=10.5 and 3.60 Hz, CH—NH), 7.05 (1H, s, NH), 7.16–7.50 (10H, m, Ar—H). δC 20.8, 23.7, 24.9, 41.8, 58.8, 89.1, 125.9, 126.3, 127.6, 127.8, 128.1, 128.3, 139.3, 142.5 (Ar), 158.8 (C═O). νmax (cm−1): 3261, 3160 (N—H), 2955, 2869 (methyl and methylene C—H), 1752, 17235 (C═O), 1495, 1447 (Ar C═C), 1251 (C—O). m/e 313 (MNH4+, 12%), 296 (MH+, 15%), 237 (100%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=O)(C)(C)C.[Br:28][C:29]1[CH:42]=[CH:41][C:32]2[CH:33]=[C:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][O:36][C:31]=2[CH:30]=1>>[Br:28][C:29]1[CH:42]=[CH:41][C:32]2[CH:33]=[C:34]([S:37]([NH:8][C@H:9]3[CH2:13][CH2:12][N:11]([NH:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]5[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=5)[CH2:19][CH2:20]4)[C:10]3=[O:27])(=[O:38])=[O:39])[CH2:35][O:36][C:31]=2[CH:30]=1
Reactant: O=S(=O)(Cl)C1=Cc2ccc(Br)cc2OC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Product: O=C1[C@@H](NS(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCN(c2ccncc2)CC1
Yield: 30.5 %

Procedure:
Similarly to Example 86 and using (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-pyrrolidone (220 mg) and 7-bromo-2H-benzopyran-3-sulfonyl chloride (161 mg), the title compound (87 mg) was obtained as a colorless amorphous material.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([SH:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]3[O:40][CH2:39]3)[C:33]([O:35]C)=[O:34])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]([OH:40])[CH2:39][S:11][C:9]3[S:10][C:6]4[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=4[N:8]=3)[C:33]([OH:35])=[O:34])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: CCOc1ccc2nc(S)sc2c1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: CCOc1ccc2nc(SCC(O)CC(NS(=O)(=O)c3ccc(-c4ccc(OC)cc4)cc3)C(=O)O)sc2c1

Procedure:
Example 25 is prepared from 6-ethoxy-2-mercaptobenzothiazole and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37]2)(=[O:33])=[O:32].N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1])(=[O:32])=[O:33]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (75 mg, 0.262 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (84 mg, 0.236 mmol) were dissolved in 2.5 ml of ethanol, and added with 42 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-yl idene)methyl)-3-methyl-5-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 66 (117 mg, yield 79.6%) as an orange solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:46])(=[O:45])[N:43](COCC[Si](C)(C)C)[C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:45])(=[O:46])[NH:43][C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-{4-[6-(2-Cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (17 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{3-[2-{4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N+:18]([O-])=O)=[CH:6][C:7]([F:17])=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:9]=1)[CH3:2].[C:21]([CH2:23][C:24](OCC)=O)#[N:22]>CO.[Pd]>[CH2:1]([N:3]1[C:4]2[CH:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:7]([F:17])=[CH:6][C:5]=2[N:18]=[C:24]1[CH2:23][C:21]#[N:22])[CH3:2]
Reactant: CCNc1cc(N2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CC#N
Agent: [Pd]
Solvent: CO
Product: CCn1c(CC#N)nc2cc(F)c(N3CCN(C)CC3)cc21
Yield: 38.8 %

Procedure:
1-[5-(Ethylamino)-2-fluoro-4-nitrophenyl]-4-methylpiperazine (2.8 g, 10 mmol) is dissolved in methanol (200 ml) and hydrogenated with 5 percent palladium/carbon under hydrogen at normal pressure. The palladium/carbon is filtered off and the filtrate is evaporated under reduced pressure. The residue is dried in a high vacuum, dissolved in diethyl glycol ethyl ether (10 ml) and then treated with ethyl cyanoacetate (2.26 g, 20 mmol). The solution is heated to 160° for 4 hours. The solvent is then distilled off and the residue is taken up in an acetic acid/ether mixture (100 ml, 1:2). The crystals obtained are filtered off, dissolved in an ethyl acetate/methanol mixture (6:4 and chromatographed on silica gel (eluent: ethyl acetate/methanol 6:4). The product is recrystallized from an ethyl acetate/acetonitrile mixture (9:1). There are obtained 1.17 g (39%) of 1-ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-2-benzimidazoleacetonitrile with a m.p. of 204°-206°.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:16])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)=O.[BH4-].[Li+]>O1CCCC1.O>[C:12]([O:11][C:9]([N:7]1[CH2:8][C:5]([CH2:3][OH:2])([CH3:16])[CH2:6]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO2006/73361 A1, 2006) (1.1 g) is dissolved in 20 mL of tetrahydrofurane. Lithiumborohydride (16.8 mL of a 2 M solution in tetrahydrofurane) is added dropwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water, washed with a saturated ammonium chloride water solution and the organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (hexane/ethyl acetate 100:0→50:50) to give the title compound. Yield: 970 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.[C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][N:23]([CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:28](=[O:30])[CH3:29])[CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCNCC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCCN1CCCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS401 starting from 68 mg (0.19 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pyridin-2-yl]-1,4-diazepane and 34 μl of bromobutyl acetate using 2 equiv. of potassium carbonate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([SH:34])=[N:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([S:34][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]3)=[O:23])=[N:4][CH:3]=2)=[N:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)c1cnc(S)n1C
Product: CCOC(=O)c1cnc(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCC(C)CC3)s2)n1C

Procedure:
Prepared as described in general procedure (E) from 3-(5-bromothiazol-2-yl)-1-cyclohexyl-1-(4-methylcyclohexyl)-urea (Example 242) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]([CH3:17])[CH:15]=O>>[CH3:13][N:14]([CH3:17])/[CH:15]=[CH:1]/[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN(C)C=O
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Product: CN(C)/C=C/c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 66 %

Procedure:
The procedure was adapted from that reported J. Org. Chem. 1978, 43, 2536. Dimethylfomamide-dimethyl acetal (4 mL, 30.05 mmol) was added to a warmed (80°) suspension of 6-methyl-5-nitropyrimidine-2,4(1H,3H)-dione (3 g, 17.54 mmol) in dimethylformamide (10 ml). The resultant mixture was heated to 140° for 30 min then allowed to cool to room temperature. The solid was collected by filtration and washed with ethyl acetate then dried in vacuo to afford 6-[(e)-2-(dimethylamino)vinyl]-5-nitropyrimidine-2,4(1H,3H)-dione (2.62 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.O=S(Cl)[Cl:26]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21]([Cl:26])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid (400 mg, 1.18 mmol) in SOCl2 (10 mL) was added 3 drops of DMF and the suspension was stirred at ambient temperature overnight. The suspension was filtered and washed with CH2Cl2 and the white solid was dried in under reduced pressure to give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: CON(C)C(=O)c1cc(F)ccc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Bromo-5-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 0.015 mol) was dissolved in THF (30 mL) and the solution was cooled to 0° C. under N2blanket. Methyl magnesium bromide (15.26 mL, 0.046 mol) was added dropwise over 30 min. The solution was warmed to room temperature and stirred for 1 hour. The solution was cooled to 0° C. and quenched with HCl/EtOH (9 mL, 4 M solution). The reaction mixture was transferred to a separatory funnel, diluted with H2O (30 mL), and extracted with Ethyl Acetate (2×40 mL). The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. The solution was concentrated to afford 1-(2-bromo-5-fluorophenyl)ethanone as a yellow oil in 93% yield. This material was used in the subsequent step without further purification. 1H NMR (CDCl3, 500 MHz) δ2.61 (s, 3H), 7.00-7.04 (m, 1H) 7.15-7.18 (m, 1H), 7.53-7.59 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1)=[O:14])=[O:9]
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A mixture of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) and triethylamine (0.14 ml, 1 mmol) in dry acetone (10 ml) was stirred at room temperature for 30 minutes. A solution of 3-bromophtalide (213 mg, 1 mmol) in acetone (2 ml) was added under ice cooling, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was filtered by suction, and the solvent was removed from the filtrate. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate, then with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (developing solvent: benzene:ether=49:1). The pale yellow second eluate was collected. After removing the solvent, the resulting oily product was crystallized with isopropyl ether to give the desired compound (159 mg, yield, 39%). m.p., 194°-195° C. (white crystals, recrystallized from benzene-n-hexane)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:35]=3)=[CH:30][CH:29]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)[N:15]=1)([CH3:10])[CH3:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:35]=3)=[CH:30][CH:29]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
A mixture of 1,1-dimethylethyl 2-{2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazol-4-yl}pyrrolidine-1-carboxylate (200 mg) and 5 mL of 50% TFA in DCM was stirred at room temperature for 20 min. After concentrated in vacuo, the reaction mixture was separated by prep HPLC to give 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole (150 mg): 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (m, 1H), 1.9 (s, 3H), 2.2-2.6 (m, 4H), 3.2 (s, 3H), 3.4 (m, 2H), 4.7 (m, 1H), 7.1 (m, 1H), 7.2 (m, 5H), 7.4 (s, 1H), 7.7 (m, 3H), 8.0 (m, 2H), 8.2 (m, 1H); LC/MS M+H 520 (observed).
Reaction SMILES: [C:1]([O:5][C:6](=[O:78])[C@@H:7]([NH:13][C:14](=[O:77])[CH2:15][CH2:16][C@@H:17]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[NH:18][C:19](=[O:69])[CH2:20][CH2:21][C@@H:22]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[NH:23][C:24](=[O:61])[CH2:25][CH2:26][C@@H:27]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH:28][C:29](=[O:53])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:92]1[C:97](=[O:98])[CH2:96][CH2:95][C:93]1=[O:94])=[N+](C)C)C>C(#N)C>[O:94]=[C:93]1[CH2:95][CH2:96][C:97](=[O:98])[N:92]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][C@H:7]([NH:13][C:14](=[O:77])[CH2:15][CH2:16][C@@H:17]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[NH:18][C:19](=[O:69])[CH2:20][CH2:21][C@@H:22]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[NH:23][C:24](=[O:61])[CH2:25][CH2:26][C@@H:27]([C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[NH:28][C:29](=[O:53])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:78]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
(S)-2-((S)-4-tert-Butoxycarbonyl-4-{(S)-4-tert-butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}butyrylamino)pentanedioic acid 1-tert-butyl ester (0.1 g, 0.09 mmol) was activated with TSTU (29.8 mg, 0.099 mmol) in acetonitrile solution at RT for 1 h using the same method for activation and work up as described above. This afforded 100 mg crude activated product which could be used as such for insulin acylation without further purification. LC-MS (electrospray): m/z=1208 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.