Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(O)(=O)C.O1CCCC1>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 50 °C
Yield: 94.7 %

Procedure:
52.95 g (0.2 mol) of 7-amino-1-(ethoxycarbonylmethyl)quinoxaline-2,3(1H,4H)-dione and a spatula tip of 4-(N,N-dimethyl-amino)pyridine were suspended in a mixture of 500 ml of glacial acetic acid and 300 ml of tetrahydrofuran and heated to 50° C. Then 20.5 g (0.2 mol) of acetic anhydride were added dropwise, and the mixture was heated at 50° C. for 2 h. The precipitate was filtered off with suction. 57.8 g (94%) of the product were obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([C:21]#[N:22])=[N:8][C:9]([S:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[CH:10][CH:11]=1.O.O.Cl[Sn]Cl>O.S(=O)(=O)(O)O.Cl>[Cl:19][C:17]1[CH:18]=[C:13]([S:12][C:9]2[N:8]=[C:7]3[C:21]([NH2:1])=[N:22][NH:5][C:6]3=[CH:11][CH:10]=2)[CH:14]=[C:15]([Cl:20])[CH:16]=1
Reactant: O=N[O-]
Reactant: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1n[nH]c2ccc(Sc3cc(Cl)cc(Cl)c3)nc12
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
A solution of 350 mg of NaNO2 (5.07 mmol) in water (2 ml) is added to a stirring solution of 1.5 g of 3-amino-6-(3,5-dichlorophenylthio)picolinonitrile (5.07 mmol) in 100 ml of 50% sulfuric acid at 0° C. The mixture is stirred for 20 minutes at 0-5° C. A solution of 2.9 g of SnCl2.2H2O (12.7 mmol, 2.5 eq) in hydrochloric acid (12 N solution, 10 ml) is then added and the solution is stirred for 1 hour at room temperature. The solid formed is filtered and then washed twice with 20 ml of water. The solid is suspended in 100 ml and the pH is adjusted to 10 by adding 30% soda solution. The organic phase is separated and then dried on anhydrous sodium sulfate before being concentrated under vacuum. A light yellow solid is obtained after recrystallization in ethyl acetate (470 mg, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH2:14](I)[CH3:15].N1C=CC=CC=1>C(O)(C)C>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCI
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CCNc1ccc(CC(=O)OCC)cc1
Yield: 32 %

Procedure:
Ethyl p-aminophenylacetate (5.4 g), ethyl iodide (4.7 g), pyridine (2.4 g) and isopropanol (50 ml) are boiled together during 6 hours. The reaction mixture is concentrated in vacuo, taken up into water, extracted with ether and dried, and the solvent is then removed. Ethyl p-ethylaminophenylacetate (2 g) is isolated by chromatography over silica. Saponification in the cold, in methanolic sodium hydroxide, gives 1.2 g of p-ethylaminophenylacetic acid. M.p. inst. = 123°C after recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrCCCCCBr
Reactant: COc1ccc(CCCO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCCOCCCCCBr)cc1
Yield: 244.6 %

Procedure:
4-Methoxybenzenepropanol (7.5 g) and 1,5 dibromopentane (30.5 g) were stirred rapidly at RT with tetra-n-butylammonium bisulphate (1.02 g) and 12.5M aqueous NaOH (36 ml) for 16 h. The mixture was diluted with H2O (170 ml), extracted with ER (3×200 ml) and the combined organic extracts were washed consecutively with H2O (170 ml) and BR (170 ml), dried and evaporated to give an oil (34.8 g). The oil was purified by [FCS] eluting with ER-CX (0:100→4:96) to give the title compound as a colourless oil (8.83 g). T.l.c. (CX-ER 79:1) Rf 0.1.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][N:7]=1.[C:18](OC(=O)C)(=[O:20])C.NC1C=CC=CC=1CCC1C=CC=CN=1>C(O)=O>[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[NH:1][CH:18]=[O:20])=[N:7][CH:8]=1)[CH3:13]
Reactant: CCc1ccc(CCc2ccccc2N)nc1
Reactant: CC(=O)OC(C)=O
Agent: Nc1ccccc1CCc1ccccn1
Solvent: O=CO
Product: CCc1ccc(CCc2ccccc2NC=O)nc1

Procedure:
Reaction of 2-(o-aminophenethyl)-5 -ethylpyridine with acetic anhydride and formic acid according to the procedure described in Example 2 (b) for 2-(o-aminophenethyl)pyridine provides the formylated product 5-ethyl-2-(o-formamidophenethyl)pyridine which can be crystallized from isopropyl ether, m.p. 62° -63.5° C. (corr.).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=1)[O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1.[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][C:50]([C:63](O)=[O:64])=[CH:51][CH:52]=2)[N:47]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:57][CH2:58][N:59]([CH3:62])[CH2:60][CH2:61]2)[C:53]2[C:48](=[CH:49][C:50]([C:63]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=3)[O:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:64])=[CH:51][CH:52]=2)[N:47]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COC(=O)c1ccc(Oc2cccc(CN)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Oc2cccc(CNC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)c2)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of methyl 4-[3-(aminomethyl)phenoxy]benzoate-HCl (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-Dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=10) to give the desired product (0.020 g, 50%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): δ 9.16 (m, 1H), 7.89 (d, 2H), 7.70 (m, 2H), 7.36 (m, 2H), 7.14 (d, 1H), 6.99 (d, 2H), 6.95 (m, 2H), 6.39 (bs, 2H), 4.44 (d, 2H), 3.75 (s, 3H), 3.50 (bs, 4H), 3.29 (s, 4H), 2.18 (s, 3H); Analytical LCMS (M+H)+: m/z=527.0.
Reaction SMILES: Br[CH2:2]/[C:3](/[C:11]([O:13][CH3:14])=[O:12])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:15]([O-:18])([O-:17])=[O:16].[Na+:19].[Na+].[Br-].[Na+].[K+].[Br-]>O.CO>[Na+:19].[C:11](/[C:3](=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:2][S:15]([O-:18])(=[O:17])=[O:16])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)/C(=C/c1ccccc1)CBr
Reactant: O=S([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a 12 L, 3-neck round bottom flask fitted with a mechanical stirrer, thermometer and an addition funnel was added the resultant product from Example 3B (400 g, 1.57 mol) and methanol (4 L). The mixture was warmed to 50° C. and a solution of sodium sulfite (199 g, 1.57 mol) dissolved in water (4 L) was added over 75 min while the internal temperature of the flask was maintained at 50° C. After the addition was complete, the clear solution was allowed to stir at 50° C. for an additional 45 min. The reaction mixture in solution was taken to the next step without additional purification. The compound may be isolated by concentration to an amorphous powder, which is contaminated with an equivalent of sodium bromide: IR (KBr) 1711, 1628, 1215 cm-1 ; 1H NMR (DMSO D-6) δ3.70 (s, 3H), 3.77 (s, 2H), 7.33-7.41 (m, 3 H), 7.48 (s, 1H), 7.87-7.89 (m, 2H); 13C NMR (75 MHz, DMSO D-6) δ49.88, 51.93, 127.36, 128.33, 128.91, 129.82, 134.75, 139.06, 168.60.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])#[N:2].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>>[CH3:18][N:19]([CH3:23])[C:20](=[S:21])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:16][CH:15]=1
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccccc1C(=O)c1ccc(O)cc1
Product: CN(C)C(=S)Oc1ccc(C(=O)c2ccccc2C#N)cc1
Yield: 90.1 %

Procedure:
Following the procedure described in Preparation I and starting from 13.3 g (0.059 mol) of 2-cyanophenyl 4-hydroxyphenyl methanone and 8.5 g (0.068 mol) of dimethylthiocarbamoyl chloride, 16.5 g (yield: 89%) of O-4-(2-cyanobenzoyl)phenyl dimethylthiocarbamate melting at 138° C. are obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22](O)=[O:23])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.Cl.[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32]>>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:31]([C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:23])[CH2:37][CH2:38]1)=[O:32]
Reactant: COCCNC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Agent: Cl
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A77) and trans-4-amino-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide hydrochloride (A196) the title compound is obtained as colorless solid.
Reaction SMILES: OCC[CH:4]1[C:9]2([O:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:15]1(=O)CCCCC1>>[CH2:8]1[C:9]2([O:10][CH2:15][CH:11]=[CH:12][CH2:13][O:14]2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: OCCC1CCCCC12OCCCO2
Product: C1=CCOC2(CCCCC2)OC1

Procedure:
Described herein is a process for the preparation of 9 (2-hydroxyethyl)-7, 11-dioxaspiro (5,5) undecane by reacting Cis-but-2-2ene-1,4 diol with cyclohexanone in the presence of a heterogeneous sulphonated nitro coal acid catalyst to obtain 7, 12-dioxaspiro (5,6) dodec-9-ene which is reacted with syngas in the presence of a catalyst, namely RhH (CO) (TPP)3, to obtain 9-formyl-7, 12-dioxaspiro (5,6) dodecane which is reduced and the reduced product is rearranged to yield 9-(2-hydroxyethyl)-7,11-dioxaspiro [5,5] undecane.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd]>[C:20]1([NH:19][C:17]2[N:16]=[CH:15][C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCc3cnc(Nc4ccccc4)nc3CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: c1ccc(Nc2ncc3c(n2)CCNCC3)cc1
Yield: 77 %

Procedure:
150 mg (7-benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-phenyl-amine and 20 mg palladium on charcoal in 10 mL was stirred 1 day under 3 bar of a hydrogen atmosphere. The mixture was filtered and evaporated to yield 84 mg of the desired product. (M+H)+=241
Reaction SMILES: [CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([OH:27])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:57]([N:60]=[C:61]=[O:62])([CH3:59])[CH3:58]>ClC(Cl)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH3:58][CH:57]([NH:60][C:61](=[O:62])[O:27][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]2[O:28][C@H:29]3[CH2:35][N:32]([C:33](=[O:34])[C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:7][C:8](=[O:56])[O:9][C@@H:10]4[CH2:55][CH2:54][CH2:53][C@H:11]4[CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][C:17]=12)[C@H:31]([C:36](=[O:37])[NH:38][C@:39]1([C:44](=[O:52])[NH:45][S:46]([CH:49]2[CH2:50][CH2:51]2)(=[O:47])=[O:48])[CH2:41][C@H:40]1[CH:42]=[CH2:43])[CH2:30]3)[CH3:59]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)N=C=O
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OC(=O)NC(C)C)O2)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OC(=O)NC(C)C)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 50 °C

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 17) (30 mg) in dichloroethane (0.6 mL) was added isopropylisocyanate (0.037 mL) then DMAP (4.6 mg). The reaction mixture was heated to 50° C. for 1 hour. After cooling back to room temperature, the mixture was diluted with ethyl acetate and water was added. The mixture was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40% ACN-100% ACN/0.05% TFA/water) yielded 27 mg of the desired product after workup with NaHCO3 and ethyl acetate. HRMS (ES+) m/z 875.3981 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([N:3]1[C:2]([CH3:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnn(Cc2ccccc2)c1C
Temperature: 20 °C
Yield: 43.4 %

Procedure:
To a solution of methyl 3-methyl-1H-pyrazole-4-carboxylate (280 mg, 2 mmol) in N, N-dimethylformamide (30 mL) was added (bromomethyl)benzene (0.34 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20° C. and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by CXTH (Column: Dsisol, 10 μM, C18, 250 mm*50 mm; Mobile: acetonitrile (0.1% formic acid)-water (0.1% formic acid), acetonitrile from 30% to 70% in 80 minutes; oven: 20° C.; flow rate: 50 mL/minute, wavelength: 214 nm) to give crude methyl 1-benzyl-5-methyl-1H-pyrazole-4-carboxylate (200 mg, 42%). LRMS (M+H+) m/z: calcd. 230.11. found 230.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:51][O:52][C:53]1[CH:60]=[CH:59][CH:58]=[CH:57][C:54]=1[CH:55]=O>>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH2:55][C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=3[O:52][CH3:51])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccccc4OC)nc32)[C@H](O)[C@@H]1O
Yield: 21.7 %

Procedure:
The title compound was prepared by a similar method to example 5 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (200 mg, 0.4 mmol), sodium triacetoxyborohydnde (152 mg, 0.72 mmol) and 2-methoxybenzaldehyde (75 mg, 0.53 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5), which gave the title compound (53 mg) as a foam. MS: 611 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1>C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:32]=2)=[O:18])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: O=C(NCc1ccccc1)Nc1nc(C(=O)O)cs1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1
Reaction time: 20 h
Yield: 51 %

Procedure:
419 mg of 2-(3-benzyl-ureido)-thiazole-4-carboxylic acid, 265 mg of CDMT, 4.5 ml of THF and 0.18 ml of N-MM are 4.5 hrs. at RT. After the addition of 350 mg of ethyl 4-amino-phenyloxyacetate hydrochloride and 0.18 ml of N-MM the mixture is stirred for a further 20 hrs. at RT. For the working up, the mixture is diluted with ethyl acetate and washed in succession with dilute hydrochloric acid, water, dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and evaporated in a vacuum. Chromatography on silica gel with methylene chloride-alcohol 99:1 and crystallization from ether gives 350 mg of ethyl (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-phenoxy)-acetate, m.p. 173° C., MS: 455 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CC(=O)CC>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: ClCCCBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
253.7 g (1.27 mol) 4-hydroxybenzophenone was dissolved in 2.56 l 2-butanone. 884.5 g (6.3 mol) potassium carbonate and 201.5 g (1.27 mol) 1-bromo-3-chloro-propane were added. The mixture was refluxed for 16 hours. The mixture was allowed to cool down to room temperature and the inorganic salts were removed by filtration. The solvent was removed under reduced pressure. The residue was treated with 250 mL acetone and 600 mL isopropyl acetate. The residue partially solidified. The solvent was removed and the residue was treated with 1.5 L water. The crude 4-(3-chloropropoxy)benzophenone crystallized from the medium, was isolated by filtration and dried. 228 g of the crude 4-(3-chloropropoxy)benzophenone was isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:18]=[C:19]=[S:20])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:19](=[S:20])[N:18]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1)[C:4]2=[O:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: S=C=NCC1CCCO1
Solvent: CCO
Product: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (8.0 g, 37.0 mmol), tetrahydrofurfuryl isothiocyanate (5.0 g, 34.9 mmol) and triethylarine (5.0 mL, 3.6 g, 35.6 mmol) in ethanol (48 mL) was heated at reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and filtered. The resulting filter cake was washed with 50 mL of cold ethanol, followed by 50 mL of hexanes to provide 10.8 g of the title compound of Step A as a solid melting at 230-232° C. IH NMR (400 MHz, Me2SO-d6): δ 1.63-2.0 (m,4H), 3.58-3.68 (m,1H), 3.74-3.82 (m,1H), 4.32 (dd,1H), 4.39-4.50 (m,1H), 4.58 (dd,1H), 7.37 (d,1H), 7.91 (d,1H), 8.02 (s,1H), 13.1 (br s,1H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH3:45])[C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH3:45])[C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-ethylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]#[C:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])=[CH:14][CH:13]=1)[C:5]([CH3:9])([S:7][CH3:8])[CH3:6].[OH:29]O>C(#N)C.O>[OH:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:10][C:11](=[O:27])[C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]#[C:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])=[CH:16][CH:17]=1)[C:5]([CH3:9])([S:7]([CH3:8])=[O:29])[CH3:6]
Reactant: CSC(C)(C)[C@H](NC(=O)c1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)C(=O)NO
Reactant: OO
Solvent: O
Solvent: CC#N
Product: CS(=O)C(C)(C)[C@H](NC(=O)c1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 89800 %

Procedure:
To a stirring solution of N—((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (3, 0.2 g, 0.50 mmol) in acetonitrile/water (20 mL) was added 30% aqueous hydrogen peroxide (0.015 mL, 0.50 mmol) and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was lyophylized to afford N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (4, 200 mg, 449 mmol, 90%). MS: m/z calcd for C21H24N2O5S 416.14. found [M+H]+ 417.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]([CH:8]=O)[CH2:2]2.[NH2:10][OH:11]>>[CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]([CH:8]=[N:10][OH:11])[CH2:2]2
Reactant: NO
Reactant: O=CC1CCC2CC2C1
Product: ON=CC1CCC2CC2C1

Procedure:
Bicyclo[4.1.0]heptane-3-carbaldehyde oxime (I-12D) was prepared by reaction of bicyclo[4.1.0]heptane-3-carbaldehyde and hydroxylamine following the same procol as described for I-6c. MS m/z 140.1 (M+1).