Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1>CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([I:1])[C:7]([NH2:10])=[N:8][CH:9]=1
Reactant: II
Reactant: Nc1ccc(Br)cn1
Solvent: CS(C)=O
Product: Nc1ncc(Br)cc1I
Temperature: 100 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
I2 (8.81 g, 34.7 mmol, 1.2 equiv.) was added to a solution of 5-bromopyridin-2-amine (5.00 g, 28.9 mmol) in DMSO (30 mL), and the resulting mixture was stirred at 100° C. for 4 h. After standing at 25° C. for 12 h, the reaction mixture was poured onto a saturated Na2S2O5 aqueous solution (20 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 15 to 25%) providing 5-bromo-3-iodopyridin-2-amine (4.00 g, 46%) as a pale yellow solid. H1 NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.98 (s, 1H) and 5.05 (bs, 2H). K2CO3 aqueous solution (1 M, 6.8 mL) was added to a suspension of 5-bromo-3-iodopyridin-2-amine (2.00 g, 6.69 mmol), 6-methoxypyridin-3-ylboronic acid (1.12 g, 7.32 s mmol, 1.1 equiv.), and Pd(PPh)3 (380 mg, 5 mol %) in dioxane (20 mL) under N2. The reaction mixture was stirred at 120° C. for 14 h, poured onto H2O (65 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 30 to 40%) providing intermediate 5-bromo-3-(6-methoxypyridin-3-yl)pyridin-2-amine (1′) (Formula iv) (993 mg, 53%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:23](=[O:24])[N:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([CH2:17]I)[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(Cl)Cl>C1COCC1>[C:1]([NH:9][C@@H:10]1[C:23](=[O:24])[N:12]2[CH:13]([C:19]([O:21][CH3:22])=[O:20])[C:14](=[CH2:17])[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(CI)CS[C@@H]2[C@H](NC(=O)c3ccccc3)C(=O)N12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C=C1CS[C@@H]2[C@H](NC(=O)c3ccccc3)C(=O)N2C1C(=O)OC
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 65 %

Procedure:
To 48 ml of a solution of SmI2 in THF (0.1M) a solution of 1 g of methyl 7β-benzoylamino-3-iodomethyl-3-cephem-4carboxylate in 100 ml of dry THF, was added by dropping at -78° C. The resulting mixture was allowed to warm to room temperature in 0.5 hours. Water was added, and the mixture stirred for further 0.2 hours at room temperature. Methylene chloride was added, and the organic phase was separated, washed with brine, dried, and evaporated in vacuo. After column chromatography the title product was isolated in 65% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38](O)=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[N:3]=1.[CH:46]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:48][CH2:47]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:52][S:49]([CH:46]6[CH2:48][CH2:47]6)(=[O:51])=[O:50])=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[N:3]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3nc(C)cc3C)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3nc(C)cc3C)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (130) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxy quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (56): m/z=719 (M+H)+. 1H NMR (CDCl3): 0.70-0.96 (m, 1H), 1.1-1.2 (m, 5H), 1.4-1.55 (m, 2H), 1.80-1.93 (m, 4H), 2.15-2.25 (m, 1H), 2.30-2.40 (m, 2H), 3.30 (s, 3H), 2.45-2.55 (m, 2H), 2.52 (s, 3H), 2.80 (s, 3H), 2.82-2.91 (m, 2H), 3.00 (s, 3H), 3.45-3.55 (m, 2H), 3.95 (s, 3H), 4.51-4.60 (m, 1H), 4.99-5.1 (m, 1H), 5.21-5.33 (m, 1H), 5.51 (m, 1H), 6.00 (s, 1H), 7.03 (s, 1H), 7.10 (d, J=9.1 Hz, 1H), 7.20 (s, 1H), 7.98 (d, J=9.1 Hz, 1H), 10.80 (br s, 1H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.O>CS(C)=O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=[C:2]1[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1c(=O)c2c(nc(Br)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reactant: C1CCNC1
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(nc(N3CCCC3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.12 mmol) in 300 μL DMSO was treated with pyrrolidine (55 μL, 0.55 mmol) and heated at 130° C. for 15 h. The reaction was cooled to 25° C. and treated with 1 mL H2O. After centrifugation for 1 h the liquid was decanted, and the process was repeated. The reaction was treated with 1 mL toluene and concentrated under reduced pressure. The residue was treated with 2 mL CH2Cl2 followed by isocyanate scavenger resin (500 mg, 0.58 mmol, 1.16 mmol/g). The reaction was filtered after agitating for 30 min, and the filtrate was concentrated under reduced pressure to give 48 mg (>99% yield) of the title compound: 1H NMR (CDCl3, 300 MHz) 7.27-7.18 (m, 2H), 7.02-6.91 (m, 1H), 5.73 (s, 2H), 3.59-3.48 (m, 7H), 3.35 (s, 3H), 1.98-1.87 (m, 4H); MS (ESP+) m/e 392 (MH+); TLC (EtOAc:hexanes/1:1) Rf=0.24.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[NH:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)[C:8]2=[N:9][CH:10]=1)#[N:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:26]Br>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:26][N:13]1[C:7]2[C:8](=[N:9][CH:10]=[C:5]([C:3]#[N:4])[CH:6]=2)[N:11]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[C:12]1=[O:14]
Reactant: N#Cc1cnc2c(c1)[nH]c(=O)n2[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ncc(C#N)cc32)cc1Cl
Temperature: 25 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.58g) was added portionwise to a solution 6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (21 g) in N,N-dimethylformamide (210 ml) at 0° C., and the mixture was stirred at ambient temperature for an hour. After adding 3-chloro-4-methoxybenzyl bromide (20.1 g) at ambient temperature, the reaction mixture was stirred at same temperature for 3 hours and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layer was washed with water (twice) and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a silica gel column chromatography eluting with 5% methanol in chloroform and crystallization from ethanol. The crude crystals were suspended in water (400 ml) and stirred at 65° C. for 14 hours to give 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (19.9 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Clc1ccc(-c2cc(Cl)c3c(n2)CCC3)cc1Cl
Yield: 59 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with (3,4-dichlorophenyl)boronic acid (0.198 g, 1.04 mmol) to afford the title compound (0.141 g, 94%). MW=298.59. 1H NMR (CD3OD, 300 MHz) δ 8.16 (d, J=2.1 Hz, 1H), 7.90-7.84 (m, 1H), 7.69 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 3.12 (t, J=7.6 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H), 2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 297 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)=[CH:11][C:10]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)c1cc(CO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.4 g (6.99 mmol) of ({4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}oxy)(tertbutyl)dimethylsilane (Example IV) are dissolved in 10 ml of tetrahydrofuran. At room temperature, 7.68 mmol of tetrabutylammonium fluoride trihydrate (1-molar solution in THF) are added. The mixture is stirred at room temperature overnight. The solvent is then removed under reduced pressure and the product is purified by chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 3:2). This gives 2.1 g (81% of theory) of {4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]phenyl}methanol.
Reaction SMILES: [C:1]12[CH:7]([C:8]([OH:10])=O)[C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13]1>>[C:19]1([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:8]([CH:7]3[C:4]4[CH2:5][CH2:6][C:1]3=[CH:2][CH:3]=4)=[O:10])[CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C1C2=CC=C1CC2
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1C2=CC=C1CC2

Procedure:
7-Norbornadienecarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-7-norbornadienecarboxamide.
Reaction SMILES: [Br:1]Br.C(O)(=O)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([CH3:23])[CH:10]=1>O>[Br:1][C:14]1[CH:13]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11]([CH3:23])=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: BrBr
Reactant: COc1ccc(Cc2ccc(C)cc2)c(C)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)c(Cc2ccc(C)cc2)cc1Br
Temperature: 110 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Br2 was added dropwise to an acetic acid (35 mL) solution of 4-methoxy-2-methyl-1-(4-methylbenzyl)benzene while cooled on ice. The reaction mixture was stirred at 110° C. for two hours. After the reaction mixture was added with water while cooled on ice and extracted with ethyl acetate, the organic phase was washed with a saturated sodium bicarbonate aqueous solution and brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain a yellow oily title compound (4.21 g, 80%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.FC1C=CC(N2CCNCC2)=CC=1.[CH:30]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[N:39]=[N:40][C:41](Cl)=[CH:42][CH:43]=2)=[O:37])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[N:39]=[N:40][C:41]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)=[CH:42][CH:43]=2)=[O:37])[CH2:32][CH2:31]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3ncccc3C(F)(F)F)CC2)nn1
Yield: 43 %

Procedure:
Following the procedure as described in Example 1, making variation only as required to use 1-(3-trifluoromethylpyridin-2-yl)piperazine to replace 1-(4-fluorophenyl)-piperazine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 43% yield (0.061 g). 1H NMR (300 MHz, CDCl3) δ 8.44 (m, 1H), 8.01 (m, 2H), 7.89 (m, 1H), 7.02 (s, 2H), 3.88 (m, 4H), 3.54 (m, 2H), 3.41 (m, 4H), 1.51 (m, 2H), 0.78 (m, 1H), 0.45 (m, 2H), 0.07 (m, 2H). MS (ES+) m/z 421 (M+1).
Reaction SMILES: [I-].[K+].[CH3:3][C:4]([CH3:6])=[O:5].ClCC(=O)C.[CH3:12][O:13][P:14]([O:17]C)[O:15][CH3:16]>C(#N)C>[O:5]=[C:4]([CH3:6])[CH2:3][P:14](=[O:17])([O:15][CH3:16])[O:13][CH3:12]
Reactant: CC(C)=O
Reactant: COP(OC)OC
Agent: CC(=O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COP(=O)(CC(C)=O)OC
Temperature: 20 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
A 2-liter eggplant type flask was charged with 179.2 g (1.081 mol) of potassium iodide, 300 ml of acetone and 250 ml of acetonitrile, to which 100 g (1.081 mol) of chloroacetone were added, thereby forming a white suspension. Further, 134 g (1,081 tool) of trimethylphosphite were added to stir the resulting mixture for 6 hours at 20° C. and for 4 hours at 50° C. After the thus-obtained solution was filtered through Celite, the solvent was distilled off to obtain a product in the form of a brown oil. This oily product was subjected to fractional distillation under reduced pressure (at 81-85° C. and 0.02 mmHg) to obtain 127.5 g (yield: 71%) of dimethyl 2-oxopropylphosphonate. The result of analysis of this compound by 1H-NMP is described below.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH2:25][CH2:26][CH2:27][CH3:28].[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH2:25][CH2:26][CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:31]([N:30]([CH3:35])[CH3:29])(=[O:33])=[O:32])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 113 h
Yield: 11 %

Procedure:
Triethylamine (0.031 mL, 0.23 mmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (67 mg, 0.23 mmol) in dichloromethane (45 mL). The reaction mixture was cooled in an ice bath. Dimethylsulfamoyl chloride (0.025 mL, 0.23 mmol) was added. The reaction mixture was removed from the ice bath. The reaction mixture was allowed to stir at ambient temperature for ˜113 hours. Analysis by HPLC indicated that the reaction was not complete. The dichloromethane was removed under reduced pressure. 1,2-Dichloroethane (50 mL) was added and the reaction mixture was heated to 60° C. After 3 hours, more dimethylsulfamoyl chloride (2.5 μL) was added and heating was continued. After 22 hours the reaction temperature was raised to reflux and the reaction mixture was refluxed for 100 hours. The reaction mixture was extracted twice with water. The aqueous fractions were combined and concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate to provide 10 mg of N′-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N,N-dimethylsulfamide as an off-white crystalline solid, m.p. 129.5-131° C. M/Z=397.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6]/[CH:7]=[C:8](/[C:14](=[O:25])[C:15]1[CH:20]=[C:19](F)[C:18]([F:22])=[C:17]([F:23])[C:16]=1F)\[C:9]([O:11]CC)=[O:10])([CH3:5])[CH3:4].[OH-].[K+].Cl>C1COCC1>[F:23][C:17]1[CH:16]=[C:15]2[C:20]3=[C:19]([O:1][CH2:2][C:3]([CH3:5])([CH3:4])[N:6]3[CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:14]2=[O:25])[C:18]=1[F:22]
Reactant: CCOC(=O)/C(=C\NC(C)(C)CO)C(=O)c1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a solution of 7 (11.2 g, 30.8 mmol) in THF (45 mL), crushed pellets of KOH (4.32 g, 77 mmol) were added under ice-cooling. After 1.5 h, 50 mL of 10% aqueous KOH were added and the reaction mixture was heated up slowly to 85° C. and stirred for another 2 hours. The reaction mixture was acidified with 1 N HCl to pH 4. The white precipitate was collected by filtration to give 8, which was used without further purification in the next step (7.5 g, 83% yield).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18][C:17]=3[N:16]=2)C2C=CC=CC=2)C=CC=CC=1.NO.Cl>CO>[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18][C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N=C(c3ccccc3)c3ccccc3)ccc2C1
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2nc(N)ccc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Intermediate 158a was added to a round-bottomed flask. MeOH (50 mL) and NH2OH HCl (1.76 g, 25.3 mmol) was added. The resulting mixture was stirred at RT for 5 hrs. The solvents were removed in vacuo and silica gel column (MeOH:DCM=10:90) gave 158b as dark oil, 851 mg (84%, 2 steps).
Reaction SMILES: C([O:4][C:5](=[O:35])[C@@H:6]([C:25]([S:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])([CH3:27])[CH3:26])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])C=C.CNC1C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([S:8]([NH:7][C@@H:6]([C:5]([OH:35])=[O:4])[C:25]([S:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])([CH3:26])[CH3:27])(=[O:10])=[O:9])=[CH:16][CH:15]=2)=[CH:23][CH:22]=1
Reactant: C=CCOC(=O)[C@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(C)(C)SCCC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CNc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCSC(C)(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(=O)O
Reaction time: 3 h
Yield: 89 %

Procedure:
To a 0° C. solution of N-[4-(4-fluorophenoxy)benzenesulfonyl]--S--[2-(methoxycarbonyl)ethyl]-D-penicillamine allyl ester (0.36 g, 0.687 mmol) in 5 mL of ethyl acetate was added N-methylaniline followed by Pd(PPh3)4 (16 mg, 0.014 mmol). After 3 hours, the solution was concentrated, and the residue was purified by chromatography on silica gel, eluting first with 1:1 ethyl acetate:hexane and then with 10% methanol in dichloromethane to give N-[4-(4-fluorophenoxy)benzenesulfonyl]--S--[2-(methoxycarbonyl)ethyl]-D-penicillamine as a white solid in 89% yield: mp 123-124° C.; 1H--NMR(CDCl3) δ 1.27 (s, 3H), 1.35 (s, 3H), 2.40-2.82 (m, 4H), 3.71 (s, 3H), 3.94 (d, 1H, J=11 Hz), 5.60 (d, 1H, J=11 Hz), 6.93-7.82 (m, 8H); FAB HRMS: expected (M+Cs)=618.0033. Found (M+Cs)=618.0038
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([OH:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28]O)=[CH:26][CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([O:19][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)=[CH:25][CH:26]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)cc2ccccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Product: CCOC(=O)C(C)(C)Oc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc2ccccc12

Procedure:
In analogy to the procedures described in example 4D] and 4E], 2-(3-hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester (example 14C]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1I]) to give 2-methyl-2-{3-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-naphthalen-1-yloxy}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:12][N:11]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](=[O:21])[CH:9]([N:22]2C(=O)C3=CC=CC=C3C2=O)[CH2:8][S:7]1.CNN>>[NH2:22][CH:9]1[CH2:8][S:7][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:12][N:11]([CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:10]1=[O:21]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CNN
Product: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Yield: 74 %

Procedure:
Following the procedure described in Example 42(g), 0.85 g of t-butyl α-[2-(2-furyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (e) above] was dephthaloylized by treatment with methylhydrazine, to afford a crude product, which was purified by silica gel column chromatography. From the fraction eluted with a 1:1:8 by volume mixture of methanol, cyclohexane and ethyl acetate was obtained 0.45 g of the title compound as crystals, melting at 90°-92° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.O.[OH-].[Na+:24]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O-:20])=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.[Na+:24]
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccncc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.6 %

Procedure:
Methyl 2-(pyridine-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (1.14 g, 4.04 mmol) was dissolved in dioxane (15 mL) and water (5 mL) then added a solution of 2N aqueous sodium hydroxide (2.22 mL, 4.45 mmol). The reaction mixture was stirred at room temperature for 2 days then concentrated under vacuum. The remaining oil was azeotroped with toluene and dried under high vacuum to afford 1.25 g of sodium 2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate as a pale yellow oil/foam. MS (ESI, pos. ion) m/z: 269.0 (M+1).