Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:39]([N:41]([CH2:50][CH3:51])[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:40].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[OH-].[K+]>CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:47]1[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][N:41]([CH2:39][CH3:40])[CH2:50][CH3:51])[CH2:49][CH2:48]1)=[O:5]
Reactant: CCN(CC)CCN1CCNCC1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc(F)c2N)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
24 mg (0.05 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid, 8.4 mg (0.05 mmol) of 1-(2-diethylaminoethyl)piperazine, and 17 mg (0.05 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) were combined in 1.0 mL dimethyl formamide and stirred at room temperature for 48 hours. To the crude reaction was added 200 μL of a 50% w/v potassium hydroxide (aqueous) solution and the mixture was stirred for 24 hours at room temperature. The reaction was neutralized by adding a few drops of acetic acid, filtered through a 0.45 μm syringe filter, and then purified by mass-triggered reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 5.0 mg (0.01 mmol, 21% yield) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as a orange glass. 1H NMR (500 MHz, MeOD) δ 8.40 (d, 1H), 8.17 (d, 1H), 7.65 (s, 1H), 7.58 (dd, 1H), 7.42 (dd, 1H), 7.31 (t, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.07 (t, 1H), 3.86 (s, 3H), 3.70 (s, br., 4H), 2.58 (m, 12H), 1.09 (t, 6H). MS: m/z 545.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(O)(C)(C)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: NCc1ccccn1
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(Cl)nc1NCc1ccccn1
Temperature: 100 °C
Yield: 79 %

Procedure:
4 g of 2,6-dichloronicotinic acid (20.83 mmol, Aldrich) and 10.74 ml of 2-(aminomethyl)pyridine (104.17 mmol) are placed in an 80 ml sealed tube containing 40 ml of tert-butanol. The mixture is heated at 100° C. overnight and evaporated to dryness. The residue is taken up in water and the mixture is acidified by pouring in an aqueous solution of acetic acid at 10%. The precipitate is isolated by filtration and, after drying in an oven under a reduced vacuum, 4.35 g of expected product are obtained in the form of a yellow powder (yield=79%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[CH3:9].N([O-])=[O:11].[Na+]>Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH3:9]
Reactant: O=N[O-]
Reactant: Cc1cc(N)cnc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)cnc1Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 33.6 %

Procedure:
2-Chloro-3-methyl-5-nitro-pyridine (2 g, 11.6 mmol) and SnCl2.(H2O)2 (7.86 g, 34.8 mmol) are refluxed in MeOH overnight. After cooled down, the mixture is diluted with ethyl acetate, washed with water, brine, dried over MgSO4, concentrated and purified by column chromatography to afford 6-chloro-5-methyl-pyridin-3-ylamine (1.7 g). To the solution of 6-chloro-5-methyl-pyridin-3-ylamine (1.7 g, 11.6 mmol) in 1N HCl is added the solution of NaNO2 (960 mg, 13.92 mmol) in water (10 ml) slowly at 0° C. After the addition, the solution is stirred for 20 min and then heated to 90° C. for 30 min. The solution is cooled down, quenched with K2CO3, extracted with ether, dried over MgSO4, and purified by column chromatography to afford the titled compound (560 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([O:18]C)=[C:13]([F:20])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:20])[C:14]([OH:18])=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: COc1c(F)cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(F)c(O)c(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.5 %

Procedure:
To a solution of example 126 (0.122 g, 0.224 mmoles) in dichloromethane (10 ml), BBr3 (1M in dichloromethane, 1.2 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as brown solid (0.086 g, 72% yield). MP: 253-257° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.64 (s, 1H), 8.05 (s, 1H), 8.04 (dd, J=8.0, 1.4 Hz, 1H), 7.83 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.52 (t, J=5.3 Hz, 1H), 7.30 (m, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.06 (dt, J=8.7, 2.2 Hz, 1H), 6.98 (br s, 2H), 6.00 (q, J=7.0 Hz, 1H), 1.88 (d, J=7.0 Hz, 3H). Mass: 5530.14 (M++1).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([CH2:35][NH:36][C@@H:37]([CH2:41][OH:42])[C:38](O)=[O:39])=O)(C)(C)C>>[OH:42][CH2:41][C@H:37]([NH:36][CH3:35])[C:38]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:27])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:39]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)CN[C@@H](CO)C(=O)O
Agent: Cl
Product: CN[C@@H](CO)C(=O)NC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1

Procedure:
The preparation was carried out analogously starting from 50 mg (0.12 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 33 mg (0.13 mmol) of (S)-2-(tert-butoxycarbonylmethylamino)-3-hydroxypropionic acid. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off analogously using HCl in methanol.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:24]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:26])=[O:25])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CCCC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with cyclopentanesulfonyl chloride to obtain the desired product 1H NMR (300 MHz, CDCl3): δ 7.42 (dd, J=2.1 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 4.8, & 9.3 Hz, 1H), 7.25 (m, 2H), 7.10 (dd, J=9.6 & 17.7 Hz, 1H), 6.67 (br s, D2O exchangeable, 1H), 6.20 (dt, J=1.5, 8.4 & 17.4 Hz, 1H), 3.53 (p, 1H), 1.80 (m, 8H); m/z=495 [M−1]−.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:16]>C(O)C.[Pd]>[ClH:16].[ClH:16].[NH2:2][CH2:1][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)COc1cccnc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COc1cccnc1CN
Reaction time: 4 h

Procedure:
To a solution of 2-cyano-3-(ethoxycarbonylmethoxy)pyridine (3.2 g, 15.52 mmol) in 180 ml of ethanol is added concentrated aqueous HCl (2.92 ml, 35 mmol) and 10% palladium on charcoal (1.5 g). After stirring for 4 hours under a hydrogen pressure of 4 bar, the mixture is filtered through celite, rinsed with ethanol and evaporated. The 2-aminomethyl-3-(ethoxycarbonyhnethoxy)pyridine dihydrochloride thus obtained is sufficiently pure and used in the next step without further purification. Yield: 3.82 g (100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:57]=[CH:56][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:46][C@H:45]([CH2:47][O:48]CC5C=CC=CC=5)[C@@H:36]([O:37]CC5C=CC=CC=5)[C@H:27]([O:28]CC5C=CC=CC=5)[C@H:18]4[O:19]CC4C=CC=CC=4)[CH:15]=3)[NH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:3]1[CH:57]=[CH:56][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:46][C@H:45]([CH2:47][OH:48])[C@@H:36]([OH:37])[C@H:27]([OH:28])[C@H:18]4[OH:19])[CH:15]=3)[NH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c[nH]c3ccc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c[nH]c3ccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc23)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
3-(4-Ethylbenzyl)-5-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-indole: Part E (0.68 g, 0.78 mmol) was dissolved in THF (15 mL) and 25% aqueous sodium hydroxide (5 mL) and the resulting solution was brought to reflux for 3 h. After cooling to room temperature, the mixture was diluted with water (30 mL), and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:3) to provide the title compound (0.5 g, 85%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=[O:5].[BH4-].[Na+].Cl>C1COCC1>[OH:5][CH:4]1[O:6][C:7](=[O:10])[C:8]([CH3:9])=[C:3]1[O:2][CH3:1]
Reactant: COC1=C(C)C(=O)OC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=C(C)C(=O)OC1O
Temperature: 25 °C

Procedure:
2-Methoxy-3-methylmaleic anhydride (9 g), (M. M. Kayser et al, Can.J.Chem., 1986, 64, 104) in dry THF (50 mls) was added, dropwise to a suspension of sodium borohydride (1.5 g) in THF (200 mls) at 0°-5° C., over ca 30 mins. The reaction mixture was allowed to warm to room temperature for a further 30 mins. T.l.c. analysis showed no remaining starting material. The solution was carefully neutralized with 5M aqueous hydrochloric acid and then the THF removed in vacuo. The aqueous solution was extracted with ethyl acetate washed with brine and dried. After removal of solvent the crude material was purified by `flash` chromatography on silica gel eluting with 50% ethyl acetate/hexane. The title compound was obtained as a colourless crystalline solid, (6.683 g, 73%), m.p. 79° C., benzene. νmax (CH2Cl2) 3540(w), 3300 (br), 1755, 1670, 1455, 1380 and 1325cm- ; δH (CDCl 3) 1.78 (3H, s), 4.06 (3H, s), 5.96 (1H, br.s, sharpens on D2O shake) and 6.23 (1H, br.s, exch).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([F:46])=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:15]=[C:14]2[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:46][C:12]1[C:11]([NH2:10])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1)=[N:15][N:16]2[C:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reaction time: 4 h
Yield: 58.1 %

Procedure:
A total of 652 mg of {4-fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl}-carbamic acid benzyl ester obtained in Production Example II-19-b was dissolved in 20 ml of methanol, 652 mg of 10% palladium-carbon, and the mixture was subjected to catalytic hydrogenation at room temperature at normal pressure. After stirring for 4 hours, the mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 297 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]=1[C:14](=[O:16])[CH3:15].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH:20]=[CH:19]1>>[C:14]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH:20]=[CH:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)(=[O:16])[CH3:15]
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: CC(=O)c1c(Cl)cccc1N1CCNCC1
Product: CC(=O)c1c(Cl)cccc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1

Procedure:
In a manner similar to that of other examples above, 1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 455.2 (Exact Mass: 454.18).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.N1C(C)=CC=CC=1C.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:35]([C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=3)(=[O:37])=[O:36])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: Cn1ccnc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3nccn3C)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
Ethyl 7-amino-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (1 g) was dissolved in tetrahydrofuran (10 mL), then 2,6-lutidine (2.5 mL) and 1-methyl-1H-imidazole-2-sulfonyl chloride (0.98 g) were added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-100:0) to give the title compound (780 mg, yield 51%) as a white solid. MS: 566 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Si:25]([O:15][CH2:14][C@@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-N-Boc-(2S,4R)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine (500 mg) was dissolved in DMF (4.0 ml), and imidazole (164 mg) was added to the dissolution. After cooling to 0° C., tert-butylchlorodiphenylsilane (616 μl) was added to the mixture, and stirred for 1 hour. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (655 mg). Physical properties: m/z [M+H]+ 456.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:25]([O-:27])=[O:26])[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc([N+](=O)[O-])c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2[N+](=O)[O-])CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].C/C(/C)=C(/OC)\O[Si](C)(C)C.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: CCCCS(=O)(=O)Cl
Agent: COC(O[Si](C)(C)C)=C(C)C
Solvent: ClCCl
Product: CCCCS(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2, 56 mg) in dichloromethane (1 mL) were added dimethylketene methyltrimethylsilylacetal (60 mg) and 1-butanesulfonyl chloride (41 mg). The mixture was stirred for 2 days at r.t. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 9:1 to 1:1) to give butane-1-sulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a colorless solid. MS: 461.4 ([M+NH4]+)
Reaction SMILES: [Na].[CH3:2][C:3]1[NH:4][O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].I[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH3:2][C:3]1[N:4]([CH2:15][CH2:16][CH3:17])[O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCI
Reactant: CCOC(=O)c1c(C)[nH]oc1=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCn1oc(=O)c(C(=O)OCC)c1C
Temperature: 120 °C
Yield: 13.5 %

Procedure:
To a stirred solution of ethyl 3-methyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate sodium salt [prepared according G. Doleschall, Tetrahedron Lett. 1987, 28, 2993-2994] (3.5 g, 18.1 mmol) in DMF (20 mL) was added 1-iodopropane (1.70 g, 18.1 mmol). The resulting mixture was heated to 120° C. for 1 hr. When cooled down, it was poured into ice-water (30 mL), and extracted with dichloromethane (2×50 mL). The organic layer was washed with water (2×50 mL), dried over sodium sulfate, concentrated and purified by flash chromatography with ethyl acetate/hexanes (1/1) to provide a solid product (0.52 g, 13% yield). 1H NMR (CDCl3) δ ppm 4.33 (q, 2H, J=7.1 Hz), 3.86 (t, 2H, J=6.8 Hz), 2.57 (s, 3H), 1.81-1.88 (m, 2H), 1.37 (t, 3H, J=7.1 Hz), 0.98 (t, 3H, J=7.6 Hz). LCMS (APCI, M+H+): 214.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1([CH:21]([CH3:26])[C:22]([O:24]C)=O)[CH:20]=[CH:19][CH:18]=[N:17]1.Cl>O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:24])[CH:21]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)n1cccn1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(n1cccn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
A solution of 4-trifluoromethoxybromobenzene (6.3 g) in dry tetrahydrofuran (40 cm3) was added dropwise to a stirred mixture of magnesium turnings (0.62 g), dry tetrahydrofuran (10 cm3) and a crystal of iodine under a nitrogen atmosphere. The reaction commenced after about 3 cm3 of the solution had been added and the mixture was warmed gently for a few minutes. When the addition was complete the mixture was stirred for 2 hours after which a solution of methyl 2-(1H-pyrazol-1-yl)propionate (2.0 g) in dry tetrahydrofuran (5.0 cm3) was added dropwise and the mixture then stirred for a further 2 hours at the ambient temperature. Finally the mixture was warmed to 40° C. to complete the reaction. The mixture was poured into water, acidified with dilute hydrochloric acid and extracted with two portions of diethyl ether 2×50 cm3. The extracts were combined, washed with water (3×50 cm3), dried over anhydrous magnesium sulphate and concentrated by removal of the solvent by evaporation under reduced pressure. The residual oil was subjected to purification by repeated chromatographic separation on a silica gel column eluted with a mixture of petroleum ether (boiling range 60°-80° C., 4 parts by volume) and ethyl acetate (1 part by volume) to yield 1,1-bis(4-trifluoromethoxyphenyl)-2-(1H-pyrazol-1-yl)propanol (500 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[CH2:4][CH:5]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:6]=12.[H][H]>CO.ClCCl.[OH-].[OH-].[Pd+2]>[CH3:1][CH:2]1[CH:6]2[CH:5]([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:4][C:3]1=[O:17]
Reactant: [H][H]
Reactant: CC1=C2CN(C(=O)OC(C)(C)C)CC2CC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)CC2CN(C(=O)OC(C)(C)C)CC21
Yield: 91 %

Procedure:
A mixture of tert-butyl 6-methyl-5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (11.6 g, 48.9 mmol), 20% palladium hydroxide on carbon (3.43 g) in methanol (30 mL) and dichloromethane (30.0 mL) was stirred under 20 psi hydrogen for 3 h. The mixture was then filtered to remove the solid catalyst. The filtrate was concentrated. Silica gel chromatography, eluting with 5-60% ethyl acetate in hexanes, gave tert-butyl 4-methyl-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a 3 to 1 mixture of endo- and exo-isomers (10.7 g, 91% yield).