Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.74 (s, 3H), 6.77 (d, 2H, J=8.8 Hz), 7.21 (m, 2H), 7.27 (d, 1H, J=2 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.63 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.76 (d, 2H, J=5.6 Hz), 9.88 (s, 1H). MS: m/z 403.9 (M++1).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[Br:21][CH2:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:21][CH2:22][CH2:23][CH2:24][O:20][C:16]1[CH:15]=[C:14]([Br:13])[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(Br)c1
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCOc1cccc(Br)c1
Temperature: 25 °C
Yield: 67 %

Procedure:
Diethylazodicarboxylate (0.77 g, 3.8 mmol) was added to solution of 3-bromophenol (0.50 g, 3.2 mmol), 3-bromopropanol (0.53 g, 3.8 mmol), triphenylphosphine (1.0 g, 3.8 mmol) and THF (10 mL). The solution was maintained at RT for 16 h and then concentrated in vacuo. The residue was partitioned between methylene chloride and 10% NaHCO3 aq. solution and layers separated. The aqueous layer was extracted with methylene chloride (2×10 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (100 g silica gel 60, 230-400 mesh, 9:1 hexane:ethyl acetate as eluent) to give 0.63 g (71%) of the title compound as a pale yellow liquid. MS (ESI) 293.0 [M+H]+.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccc(F)cc4)CC3)n[nH]c12
Yield: 59 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with 4-fluorophenyl sulfonyl chloride (0.033 g, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.048 g of white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[Br:20][C:21]1[CH:22]=[C:23](/[C:27](/[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[C:42]#[N:43])=[N:28]\S(C(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=1>>[NH2:43][C:42]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][C:37]=2[F:41])[C:27]([C:2]2[CH:3]=[C:4]([CH3:19])[C:5]([O:17][CH3:18])=[C:6]([CH2:7][OH:8])[CH:16]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Br:20])[CH:22]=2)[N:28]=1
Reactant: COc1c(C)cc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Product: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1CO
Yield: 54 %

Procedure:
The title compound was synthesized as described for Example 35i in 54% yield, starting from of (5-bromo-2-methoxy-3-methylbenzyloxy)(tert-butyl)dimethylsilane (1.44 g, 4.17 mmol) and (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.415 g, 3.47 mmol). MS (ES+) m/z 455, 457 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]([CH:8]=[N:9][OH:10])[CH2:2]2.[Cl:11]N1C(=O)CCC1=O>>[OH:10][N:9]=[C:8]([Cl:11])[CH:3]1[CH2:4][CH2:5][CH:6]2[CH:1]([CH2:7]2)[CH2:2]1
Reactant: ON=CC1CCC2CC2C1
Reactant: O=C1CCC(=O)N1Cl
Product: ON=C(Cl)C1CCC2CC2C1

Procedure:
N-Hydroxybicyclo[4.1.0]heptane-3-carbimidoyl chloride (I-12E) was prepared by reaction of bicyclo[4.1.0]heptane-3-carbaldehyde oxime and N-chloro-succinimide following the same protocol as described for I-6B. MS m/z 174.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.CCOCC.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccc(F)cc3)c3ccccc23)CC1
Yield: 53 %

Procedure:
A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 15 ml of 4-fluorobenzoyl chloride was heated at 100° for 2 hrs. The reaction mixture was poured into ether and the precipitate was collected. The precipitate was treated with dilute aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield 2.5 g (53%) of product, mp 132°-133° C.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12](O)=O.[OH-].[Na+]>O>[CH3:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1-c1nc2ccccc2[nH]1
Temperature: 140 °C
Yield: 74.2 %

Procedure:
Benzene-1,2-diamine (2.60 g, 25 mmol) and 2-methyl-5-nitrobenzoic acid (5.0 g, 27.6 mmol) were suspended in polyphosphoric acid (30 ml, 11 vol) and heated to 140° C. overnight. Once the reaction had gone to completion (monitored by LCMS), the crude green mixture was dissolved in water, basified with NaOH (pH. 14) and extracted into EtOAc (x 2). The organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 7 (4.70 g, 74%) as an orange/brown solid: 1H NMR (C2D6SO) δ 13.20 (s, 1H), 8.80 (app d, 1H), 8.84 (dd, 1H), 7.89-7.87 (m, 2H), 7.74 (d, 1H), 7.40-7.45 (m 2H), 2.90 (s, 3H); MS (ES, positive mode): 254 [M++1].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>COCCOC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:20])(=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C(C)C)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: CC(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of methyl 7-(4-isopropylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (600 mg) in 1,2-dimethoxyethane (20 ml) was added at room temperature 6N hydrochloric acid (10 ml), and the mixture was refluxed for 24 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with hexane to give colorless crystals of 7-(4-isopropylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (555.2 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([I:10])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:18])=[O:19])=[CH:4][C:5]2[O:9][C:8]([I:10])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(I)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a suspension of 5-bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (177 mg, 90% purity, 0.34 mmol) and K2CO3 (140 mg, 1.01 mmol) in DMF (3 mL) was added dropwise CH3I (79 mg, 0.68 mol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 1 hour. After concentrated in vacuum, the residue was suspended in H2O and extracted with DCM. The residue was purified by column chromatography (eluted with DCM:EtOAc from 10:1 to 2:1) to give 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.66 (s, 1H), 6.27 (s, 1H), 3.32 (s, 3H), 3.08 (d, J=4.8 Hz, 3H), 2.89 (s, 3H). MS (M+H)+: 487/489.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:25])[CH3:24]>CS(C)=O>[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([CH3:20])=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:25])[CH3:24]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C

Procedure:
7-Benzyl-3,8-dimethylxanthine (500 mg, 1.85 mmol) was added to a suspension of sodium hydride (50.5 mg) in anhydrous DMSO (20 ml) and stirred for 30 min. (R)-5-acetoxy-1-chlorohexane (357 mg) (prepared according to Kline et al. U.S. Pat. No. 5,629,423 (1997)) was added and the mixture was heated at 70-80° C. for 12 h. After cooling to room temperature, the reaction was quenched by the addition of water (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with water (2×50 ml), with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (silica gel) eluting with ethyl acetate. Yield=638 mg.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[O:4][CH:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=3)[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2occ(Br)c2c1
Reactant: CSc1ccc(B(O)O)cc1
Product: CCOC(=O)c1cnc2occ(-c3ccc(SC)cc3)c2c1
Yield: 95 %

Procedure:
In the same manner as in Reference Example 19 and using ethyl 3-bromofuro[2,3-b]pyridine-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 95%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[C:4]([NH2:20])[N:3]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 l) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2Cl2. The product containing fraction were evaporated to yield the product (11 g). 1H NMR (DMSO-d6) δ0.84 (t, 3, CH2); 1.22 [m, 32, O--CH2 --CH2 --(CH2)16 --]; 1.86 (m, 2, O--CH2CH2 --); 3.25 (m, 2, O--CH2 --); 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H); 4.38 (t, 1, 2'H); 5.08 (d, 1, 3'-OH); 5.48 (t, 1, 5'-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1'-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H).
Reaction SMILES: I[C:2]1[C:3]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[CH:12]([NH:11][C:3]1[C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH3:8])[N:6]=[C:5]([S:9][CH3:10])[N:4]=1)([CH3:14])[CH3:13]
Reactant: C=CC(=O)OCC
Reactant: CSc1nc(C)c(I)c(NC(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C/c1c(C)nc(SC)nc1NC(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-Iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (8.1 g, 26.2 mmol), ethyl acrylate (5.24 g, 52.4 mmol), triethylamine (10.6 g, 105 mmol), palladium (II) acetate (1.17 g, 5.23 mmol), and tri-o-tolyl phosphine (1.59 g, 5.23 mmol) were added in that order to 10.8 mL of DMA in a pressure tube and sealed. The reaction mixture was heated to 100° C. and allowed to stir overnight. The reaction was quenched by filtration through a short silica plug washing with ACN. The solvent was evaporated and diluted with ethyl acetate then extracted with 10° A) aqueous LiCl, followed by water and brine. NOTE: Extraction is necessary to remove all DMA giving resolution in chromatography. The sample was purified by silica gel column chromatography using 20% ethyl acetate/hexane as eluent. Desired fractions were combined and reduced to afford 2.5 g (34% yield) of ethyl (2E)-3-[4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]acrylate as a yellow/orange oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][N:13]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])(=O)=O)=CC=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.[K]>CN(C)C=O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:22]([N:13]2[CH2:14][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][C@H:12]2[CH2:11][N:39]2[C:38](=[O:40])[C:37]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]3[C:35]2=[O:45])=[O:23])=[CH:27][CH:28]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (6.35 g: 12.27 mmole) in dimethylformamide (60 ml), potassium phthalimide (2.7 g) is added. The mixture is stirred at 70° C. for 4 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=2:1) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxy-2-phthalimidomethylpyrrolidine (4.65 g). Yield: 77.5%. NMR δ(CDCl3) ppm: 2 to 2.3(m, 1H), 2.4 to 2.6(m, 1H), 2.95, 2.97(2×s, 3H), 3.43 to 4.2(m, 5H), 3.80(s, 3H), [5.01(s)+5.07, 4.96(ABq, 12.2 Hz), 2H], 5.13 to 5.3(m, 1H). IR ν (CHCl3) cm-1 : 1774, 1716, 1613.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[CH3:30][C:31]1[CH:36]=[C:35]([NH:37][NH2:38])[CH:34]=[C:33]([CH3:39])[N:32]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:37]([C:35]2[CH:34]=[C:33]([CH3:39])[N:32]=[C:31]([CH3:30])[CH:36]=2)[N:38]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: Cc1cc(NN)cc(C)n1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cc(C)nc(C)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with (2,6-dimethyl-pyridin-4-yl)-hydrazine hydrochloride (CAS Reg. No. 1187853-32-2) to give the title compound as brown oil. MS (ESI): m/z=523.2 [M+H]
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:56]([CH2:59][CH3:60])=[C:57]=[O:58]>O1CCCC1>[CH2:59]([NH:56][C:57](=[O:58])[O:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)[CH3:60]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)O[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]-furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]py-ridin-5-yl)phenyl)cyclohexanol (50 mg) and triethylamine (20 μL) are dissolved in tetrahydrofurane (2 mL), treated with isocyanatoethane (8 μL) and stirred for 12 hours. Triethylamine (20 μL) and isocyanatoethane (8 μL) are added and the mixture is stirred for 48 hours. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 5): tR=1.26 min; Mass spectrum (ESI+): m/z=787 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CCO)cc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(CCOS(C)(=O)=O)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (0.03 M) solution of methyl 3-(2-hydroxyethyl)-1-naphthalenecarboxylate (1 eq.) from Step 2, Amine 31 and Hunig's base (1.5 eq.) was added at 0 methanesulfonyl chloride (1.3 eq.). The resulting solution was stirred at 0° C. for 30 min and then at RT for 15 min. The reaction mixture was subsequently quenched with 10% aq. HCl. The aqueous wash was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH:14]([CH3:16])[CH3:15].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH:14]([CH3:16])[CH3:15])[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCC(O)CC2)c(OC(C)C)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of methyl 4-(bromomethyl)-3-isopropoxybenzoate (2.0 g, 6.96 mmol), 4-hydroxypiperidine (1.06 g, 10.4 mmol), potassium carbonate (1.44 g, 10.4 mmol) and N,N-dimethylformamide (20 mL) was stirred at 70° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (1.77 g, yield 83%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CS(C)=O
Product: O=C(O)[C@H](Cc1ccccc1)Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
L-Phenylalanine (8.3 g, 0.05 mol) and 4.8 g (0.025 mol) of 2,5-dichloronitrobenzene were dissolved in 40 ml of anhydrous dimethyl sulfoxide (DMSO), and the stirred solution was heated to 80° C. under an argon atmosphere. Potassium tert.-butylate (4.2 g, 0.025 mol), dissolved in 30 ml of DMSO, was added dropwise in the course of 40 minutes. Stirring was continued for 3 hours at 80 to 90° C., the mixture was allowed to cool, and unreacted phenylalanine was removed by filtration with suction and washed with water. The collected alkaline filtrates were extracted twice using diethyl ether to remove unreacted dichloronitrobenzene. The mixture was then acidified using glacial acetic acid and extracted several times using ethyl acetate, and the extracts were dried over magnesium sulfate and evaporated.