Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[OH:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][NH2:24]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][OH:27])[CH2:20][CH2:19][OH:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCN(CCO)CCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCN(CCO)CCO)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
5 g of para-fluoronitrobenzene were added to a solution of 60 ml of N-methylpyrrolidinone, 6.29 g of N,N-bis(2-hydroxyethyl)ethylenediamine, and 4.3 g of triethylamine. The reaction medium was heated at 60° C. for 15 hours and, after cooling to room temperature, was poured into a water/ice mixture. A yellow precipitate formed, which was filtered off, reslurried in water, and then dried over P2O5. 7.5 g of 2-[[2-(4-nitrophenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (19) were obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[NH:23]C(=O)OC(C)(C)C)=[CH:12][C:11]=1[NH:31][C:32]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[C:34]([CH3:44])[N:33]=1)#[N:9]>C(Cl)Cl>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:13]1[CH:12]=[C:11]([NH:31][C:32]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[C:34]([CH3:44])[N:33]=2)[C:10]([C:8]#[N:9])=[N:15][CH:14]=1
Reactant: Cc1cc(-c2ccccc2)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (1.0 ml, 13 mmol) was added to a solution of tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-phenylpyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate (24 mg, 0.048 mmol) in DCM (2 ml). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to afford 5-((1R,2S)-2-aminocyclohexylamino)-3-(6-methyl-4-phenylpyridin-2-ylamino)picolinonitrile. The material was used in the next step without further purification. MS ESI calc'd. for C24H27N6 [M+H]+ 399. found 399.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]=[O:11])[CH2:9][C@H:4]2[O:3]1.[CH:13]1([Mg]Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[OH:11])[CH2:9][C@H:4]2[O:3]1
Reactant: Br[Mg]C1CCCC1
Reactant: CC1(C)O[C@H]2O[C@H](C=O)C[C@H]2O1
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2O[C@H](C(O)C3CCCC3)C[C@H]2O1
Temperature: -20 °C
Reaction time: 20 h
Yield: 21.3 %

Procedure:
To a solution of (3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (4.0 g, 23.2 mmol) in THF (20 mL) was added cyclopentylmagnesium bromide (1M in THF, 30 mL, 30 mmol) at −20° C. under argon. After being stirred at −20° C. for 20 hours, the reaction was quenched by saturated NH4Cl solution. The reaction mixture was extracted with EtOAc (30 mL) three times. The organic layers were combined and concentrated in vacuo to afford 1.2 g crude product of [(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-cyclopentyl-methanol (compound 11a) as a colorless oil, which was used in next step without further purification. MS obsd. (ESI+) [(M+H)+]: 243.
Reaction SMILES: Cl[C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CCO>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:3]3[S:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)c2sc3ccccc3c2n1
Solvent: CCO
Product: CN1CCN(c2nc(N)nc3c2sc2ccccc23)CC1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A solution of crude 4-chloro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine (30 mg, 0.13 mmol) and N-methyl piperizine (0.03 mL, 0.27 mmol) in EtOH was heated at 70° C. for 1 h. The mixture was cooled to rt and concentrated and the crude residue purified by FCC to yield a white solid (9.8 mg, 26%). MS: 300.4. 1H NMR (CDCl3): 8.34-8.27 (m, 1H), 7.81-7.75 (m, 1H), 7.57-7.51 (m, 1H), 7.48-7.43 (m, 1H), 4.85 (s, 2H), 3.98 (t, J=4.9 Hz, 4H), 2.56 (t, J=4.9 Hz, 4H), 2.37 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[NH:7][C:8]=1[Br:9].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:9][C:8]1[N:7]=[C:6]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[N:5]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:4]=1[Br:3]
Reactant: CC1(c2nc(Br)c(Br)[nH]2)CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2nc(Br)c(Br)n2COCC[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
A 250 mL round-bottom flask was purged with N2 and charged with NaH (95%, 0.33 g, 13.1 mmol). THF (15 mL) added, and the mixture cooled to 0° C. After 5 minutes, a solution of 4,5-dibromo-2-(1-methylcyclopropyl)-1H-imidazole (3.0 g, 10.7 mmol) in THF (20 mL) was added dropwise from an addition funnel over 5 minutes. The light tan solution was stirred at 0° C. for 25 minutes and SEMCl (2.1 mL, 11.8 mmol) was then added dropwise over 2 minutes. After 5 minutes, ice bath was removed, and the reaction stirred at room temperature. After stirring 2 hours, LCMS indicated 90% conversion. Another 0.3 mL of SEMCl (0.3 mL, 1.7 mmol) was added. LCMS indicates that the reaction has not proceeded; additional NaH (95%, 51 mg, 2.0 mmol) was added with concomitant gas evolution. After 15 minutes, LCMS indicated complete reaction. The reaction was quenched with water (1 mL). Heptane (250 mL) was added and organic layer was washed with water (200 mL). The aqueous layer was extracted with heptane (100 mL), and the combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to give 4.46 g of crude material. The crude material was purified by flash chromatography (SiO2; 0-25% EtOAc in heptane) to give the product (3.45 g) as a light yellow oil: LCMS(m/z) 409.0 (MH+), tR=1.27 minutes.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([NH:19][NH2:20])(=[O:18])=[O:17])=[CH:12][CH:11]=1>CO>[S:16]([NH:19][N:20]=[CH:5][C:4]1[CH:3]=[CH:2][CH:9]=[CH:8][C:6]=1[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)([C:13]1[CH:12]=[CH:11][C:10]([CH3:21])=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=Cc1ccc(F)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
4-Fluoro-benzaldehyde (26.6 ml, 31.25 g, 251 mmol) was added all at once to a stirred suspension of 4-tolylsulfonyl hydrazine (43.47 g, 287 mmol) in methanol (200 ml). Within 30 seconds everything dissolved and there was a small exotherm to 32° C., before the temperature dropped. After 30 minutes some of the solvent was evaporated. Crystallisation started after scratching and the solution was left for two hours at room temperature and overnight at ca 5° C. to crystallize. The crystals were filtered off, washed with methanol (2×ca 30 ml), then left in the air to dry, yielding 51.8 g (71%) m.p. 123-125° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[CH:37]1([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[NH2:45])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:45][C:44]([CH3:46])([C:43]([O:42][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:48])[CH3:47])[CH2:30][CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(N)C(=O)OC1CCCC1
Product: CC(C)c1cc(C(=O)N2CCC(CCNC(C)(C)C(=O)OC3CCCC3)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and α,α-dimethylglycine cyclopentyl ester. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.34 (1H, s), 5.26-5.39 (1H, m), 4.29 (2H, br. s.), 3.28 (1H, br. s.), 3.18 (1H, dt, J=13.6, 6.8 Hz), 3.03-3.12 (2H, m), 2.98 (2H, t, J=12.4 Hz), 1.64-2.01 (11H, m), 1.59 (6H, s), 1.24-1.38 (3H, m), 1.19 (6H, d, J=7.0 Hz) LC/MS: purity 97%, m/z 461 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:23]([CH:20]3[CH2:22][CH2:21]3)(=[O:25])=[O:24])[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)C4CC4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine (200 mg, 0.79 mmol) was dissolved in 2 mL pyridine and cyclopropane sulfonylchloride (118 mg, 0.79 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched by addition of 50 mL water and acetic acid until pH 5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a yellow oil (234 mg, 78%), MS: m/e=358.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.I[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: CI
Reactant: O=C(Cc1cccnc1)c1ccc(F)cc1F
Product: CC(C(=O)c1ccc(F)cc1F)c1cccnc1
Yield: 73.6 %

Procedure:
Methylation of the product of part (i) (5.0 g) with iodomethane (7.60 g) according to the method of Example 11(ii) gave the title compound as an oil (3.90 g) which was used directly in the next stage.
Reaction SMILES: ClCCl.[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)#[N:21]>N1C=CC=CC=1>[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19][S:34]([C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Reactant: N#Cc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(NS(=O)(=O)c2ccc(-c3ccc(C#N)cc3)cc2)n1
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of dichloromethane (3 mL) was added 6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (0.15 g, 0.63 mmol), 4′-cyanobiphenyl4-sulfonyl chloride (0.18 g, 0.63 mmol) and pyridine (1.0 mL). The mixture was stirred for 3 hours then was washed with saturated sodium bicarbonate (2×30 mL) and aqueous hydrochloric acid (2×30 mL, 0.1 N). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification was done using silica gel chromatography eluting with hexane: ethyl acetate (1:1) and combined fractions were concentrated to afford the above-titled intermediate as a white solid (0.21 g, 76%). HPLC: Rt4.236 min. (81% area). 1H NMR (400 MHz, CDCl3), δ: 7.89 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.52-7.49 (m, 4H), 7.43 (t, J=7.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.59 (d, J=7.3Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 4.55 (s, 2H), 0.82 (s, 9H), 0.05 (s, 6H); LRMS (ESI): m/z: 480.1.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2cccc(Cl)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 3-chloro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide as a white solid; MS: m/e=320 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[C:41]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[C:2]([C:48]3[CH:49]=[CH:50][C:45]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:46][CH:47]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 86.5 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-tert-butyl phenyl boronic acid (125 mg, 0.69 mmol) by following general procedure D yielding the title compound (95 mg) as a white solid.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1>C1COCC1>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[CH:16][CH:17]=4)=[O:11])=[C:8]([C:27]4[CH:28]=[CH:29][C:30]([C:43](=[O:44])[NH:42][C:39]5[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=5)=[CH:31][CH:32]=4)[S:7][C:6]=3[CH:34]=2)=[O:44])=[CH:38][CH:37]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(-c2sc3cc(C(=O)Nc4ccc(Cl)cc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
5.56 g (10.7 mmol) of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 200 mL of dry THF and 5.45 g (35.2 mmol) of 4-chlorophenyl isocynate was added. The reaction mixture was stirred at room temperature under an atmosphere of nitrogen. After 18 hours, the solvent was removed by evaporation in vacuo, and redissolved in CHCl3. The CHCl3 solution was cooled to -20° C. for 24 hours and the precipitate formed was filtered off. The remaining solution was chromatographed (Waters Prep 500, HPLC) on a silica gel column, eluted with a linear gradient of CHCl3 ending with CHCl3 --MeOH (19:l)(v/v). The desired fractions were determined by TLC, combined and evaporated to dryness to afford 4.01 g of the title compound as a tan amorphous powder.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:4]=[N:3][N:2]1[C:10]([NH:33][CH2:34][CH3:35])=[N:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].O.NN>CCO>[NH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:11]=[C:10]([N:2]2[N:3]=[CH:4][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:1]2)[NH:33][CH2:34][CH3:35])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: CCNC(=NS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)N1CC2(C=N1)CCCC2
Agent: NN
Solvent: CCO
Solvent: O
Product: CCNC(=NS(=O)(=O)c1ccc(CN)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Yield: 64.9 %

Procedure:
2.51 g N-[(2,3-Diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonamide was taken up in 50 mL EtOH. After addition of 0.70 mL hydrazine hydrate, the mixture was refluxed for 2 h. After cooling to room temperature, the formed precipitate was filtered off. The filtrate was concentrated, and the residue was triturated with DCM. The solids were filtered off, and the filtrate was evaporated to dryness to give 1.20 g (67%) of 4-Aminomethyl-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]benzenesulfonamide as a red oil. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.22 Hz, 3H), 1.59-1.83 (m, 8H), 3.46 (q, 2H), 3.82 (br.s., 2H), 3.92 (br.s., 2H), 6.82 (s, 1H), 7.40 (d, J=8.13 Hz, 2H), 7.88 (d, J=8.13 Hz, 2H) [NH2 & guanidine NH invisible].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:46])([CH3:45])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:34]=2[NH:33][C:32]1=[O:44].FC(F)(F)C([O-])=O>>[CH3:46][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:45])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]([F:43])([F:41])[F:42])=[CH:39][C:34]=2[NH:33][C:32]1=[O:44]
Reactant: CC(C)(N)CCn1c(=O)[nH]c2cc(C(F)(F)F)ccc21
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(CCn1c(=O)[nH]c2cc(C(F)(F)F)ccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
Prepared according to general method 1 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 287 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one. Yield: 76 mg (13%, trifluoroacetate); mass spectroscopy: [M+H]+=495.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([N:18]2[CH2:19][CH2:20][C:15]3([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:13][CH2:14]3)[CH2:16][CH2:17]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCC2(CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 130 °C
Yield: 72.1 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (150 mg, 0.93 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (244 mg, 1.02 mmol) and DIPEA (1 mL) in EtOH (3 mL) was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (50% EtOAc/isohexane) to give tert-butyl 8-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate as a yellow oil (245 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 3.76 (s, 3H), 3.49-3.39 (m, 2H), 3.30-3.00 (m, 6H), 1.90-1.60 (m, 6H), 1.55 (s, 9H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[NH:44][C:45]5[C:50]([CH:51]=4)=[CH:49][C:48]([O:52][CH3:53])=[CH:47][CH:46]=5)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:56][CH:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:55]=[CH:54][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[NH:44][C:45]4[C:50]([CH:51]=3)=[CH:49][C:48]([O:52][CH3:53])=[CH:47][CH:46]=4)=[O:42])[CH2:39][CH2:40]2)=[CH:32][CH:31]=1
Reactant: COc1ccc2[nH]c(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)cc5)cc4)CC3)cc2c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2[nH]c(C(=O)N3CCC(Nc4ccc(CCNCC(O)COc5ccc(O)cc5)cc4)CC3)cc2c1
Yield: 28.6 %

Procedure:
(4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}(5-methoxy-1H-indol-2-yl)methanone (0.128 g, 0.161 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.026 g, 0.046 mmol).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7].[CH2:26]([OH:29])[CH2:27][CH3:28].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([O:29][CH2:26][CH2:27][CH3:28])=[O:7]
Reactant: CCCO
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
2-[2-Fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionyl chloride (0.9 g; 2.3 mmole) was dissolved in dry dichloromethane and the solution was added slowly with stirring to a cooled mixture of n-propanol (5 ml) and triethylamine (1 ml). The mixture was stirred at room temperature for a period of 4 hours and then the solvent was evaporated under vacuum and the residue was dissolved in dichloromethane. The solution was washed with water and the organic phase was dried over magnesium sulfate. The solution was filtered and the solvent was removed under vacuum to give a light brown oil (0.92 g; 95.3%). The product was crystallised from ethanol to give the title compound as a crystalline solid (0.58 g; 60.4%); mp 70°-72° C. The assigned structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1>>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: Clc1cccc(CBr)c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3cccc(Cl)c3)ccc12
Yield: 7.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (162 mg, 0.77 mmol) and 1-(bromo-methyl)-3-chlorobenzene (189 mg, 0.92 mmol) to provide 472 (20 mg, 8% yield) as a white powder. LC-MS (M+H=337, obsd.=337). 1H NMR (400 MHz, DMSO-D6) δ 8.46 (m, 1H), 8.06 (d, J=8.7, 1H), 7.42 (d, J=1.7, 1H), 7.36 (dd, J=4.7, 7.8, 1H), 7.26 (m, 3H), 7.21 (d, J=6.8, 1H), 6.90 (dd, J=2.0, 8.7, 1H), 6.23 (s, 2H), 5.65 (s, 2H).