Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:41]=1[C:42](Cl)=[O:43]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:42](=[O:43])[C:41]1[C:40]([Cl:39])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:49])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 20.6 %

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35a with 91 μl (0.655 mmol) of triethylamine and 80 μl (0.561 mmol) of 2,6-dichlorobenzoyl chloride to give the title compound (I 58 mg, 56%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.62, FD-MS: M+ =599,601.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCO
Product: O=S(=O)(NCCCO)c1ccccc1
Yield: 99.5 %

Procedure:
The preparation is carried out as in Example 1(a) from 353 g of benzenesulphonyl chloride (2 mol) and 157.7 g of 3-amino-1-propanol (2.1 mol). The amount obtained is 406.7 g, i.e. a yield of 99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][C:24]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36](Br)[CH:37]=1)(=[O:31])=[O:30])([CH2:26][OH:27])[CH3:25]>>[OH:22][CH2:23][C:24]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)[CH:37]=1)(=[O:31])=[O:30])([CH2:26][OH:27])[CH3:25]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (81 mg, 0.25 mmol) (example B.4) according to general procedure II. Obtained as a yellow solid (68 mg, 50%). MS (ISP) 538.0 [(M+H)+]; mp 204-206° C.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1>CC1CCCCC1.[Pt]>[CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: c1cc2c3c(cccc3c1)CC2
Agent: [Pt]
Solvent: CC1CCCCC1
Product: C1CC2CCCC3CCC(C1)C23

Procedure:
Acenaphthene is dissolved in methylcyclohexane and then hydrogenated at 475° F. and under a hydrogen pressure of 500 p.s.i.g. using a 1% platinum-on-alumina catalyst to form perhydroacenaphthene (C12H20). After removal of most of the methylcyclohexane by distillation, the perhydroacenaphthene containing 3.3% of residual methylcyclohexane is charged in amount of 520 g. to an autoclave provided with means for effecting agitation. 70 g. of anhydrous HF are added, 30 g. of BF3 are pressured into the autoclave and the mixture is heated to and maintained in the range of 60°-100° C. and mainly in the neighborhood of 95° C. for 6.3 hours while being agitated. The reaction is then stopped, and the hydrocarbon layer is separated from the catalyst layer and washed to remove residual catalyst. Analysis of the hydrocarbon produce by vapor phase chromatography gives the results shown in Table 2.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:14](=[O:29])[C:13]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[Br:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[N:24]=[CH:23]4)[C:14](=[O:29])[C:13]=2[CH:12]=1
Reactant: ClCCN1CCCC1
Reactant: O=c1c2cc(Br)oc2ccn1-c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c2cc(Br)oc2ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.4 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (213 mg, 1.25 mmol) was added to a suspension of 2-bromo-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (187 mg, 0.570 mmol) and Cs2CO3 (1.11 g, 3.42 mmol) in anhydrous DMSO (3 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (10 mL) was added and the aqueous suspension was filtered. The solid was dried under reduced pressure. Flash chromatography on silica gel [4.75:4.75:0.5 MTBE/CH2Cl2/(9:1 EtOH/NH4OH)] afforded the title compound (113 mg, 47%) as a light yellow powder with data matching those reported in Example 9.
Reaction SMILES: B.C1COCC1.O=[C:8]1[CH:13]([CH2:14][C:15](O)=[O:16])[S:12][C:11]2[S:18][C:19]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:20][C:10]=2[NH:9]1.CO>C1COCC1>[OH:16][CH2:15][CH2:14][CH:13]1[S:12][C:11]2[S:18][C:19]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:20][C:10]=2[NH:9][CH2:8]1
Reactant: NS(=O)(=O)c1cc2c(s1)SC(CC(=O)O)C(=O)N2
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2c(s1)SC(CCO)CN2
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A solution of borane/THF (200 ml, 1M, 200 mmol) was added gradually to a solution of (2,3-dihydro-2-oxo-6-sulfamoyl-1H-thieno-[2,3-b]-[1,4]thiazin-3-yl)acetic acid (12.3 g, 40 mmol) in THF (200 ml). The mixture was stirred at ambient temperature until gas evolution ceased and the resulting clear solution was heated under reflux overnight. The reaction mixture was cooled to 25° C. and treated with methanol (200 ml). When gas evolution ceased, the mixture was evaporated to dryness under vacuum and the residue was restripped from methanol two additional times (2×50 ml). Recrystallization of the residue from water gave 6.4 g 3-(2-hydroxyethyl)-2,3-dihydro-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 145°-147° C. An additional 1.2 g of product was isolated from the filtrate on standing. Further recrystallization from water gave material of mp 149°-150° C.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[C:60]([O:84][CH3:85])=[CH:61][C:62]3[C:68](=[O:69])[N:67]4[CH:70]=[C:71]([CH3:73])[CH2:72][C@H:66]4[C:65](=[O:74])[N:64]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[C:63]=3[CH:83]=2)=[CH:52][C:12]2[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:14](=[O:43])[C@@H:15]3[CH2:21][C:20](/[CH:22]=[CH:23]/[CH2:24][NH:25]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)=[CH:19][N:16]3[C:17](=[O:18])[C:11]=2[CH:10]=1>CN(C=O)C>[NH2:25][CH2:24]/[CH:23]=[CH:22]/[C:20]1[CH2:21][C@H:15]2[C:14](=[O:43])[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:50])([CH3:49])[CH3:51])[C:12]3[CH:52]=[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]4[C:60]([O:84][CH3:85])=[CH:61][C:62]5[C:68](=[O:69])[N:67]6[CH:70]=[C:71]([CH3:73])[CH2:72][C@H:66]6[C:65](=[O:74])[N:64]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:80])([CH3:82])[CH3:81])[C:63]=5[CH:83]=4)[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[C:17](=[O:18])[N:16]2[CH:19]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(/C=C/CNC(=O)OCC4c5ccccc5-c5ccccc54)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(C)=CN1C2=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(/C=C/CN)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(C)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Piperidine (0.133 mL, 1.35 mmol, 12 eq.) was added to a stirred solution of Fmoc amine 14a (0.125 g, 0.112 mmol, 1.0 eq.) in DMF (1.8 ml). After stirring at room temperature for 30 minutes, LCMS analysis indicated consumption of starting material and the reaction mixture was diluted with DCM (200 mL) and washed with water (3×200 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness to afford the crude product which did not undergo further purification (0.100 g, assumed 100% yield). This material was used without further characterisation.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Br)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-bromophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] the desired product (0.70 mg, 9.6% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.30–7.20 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H, J=8.5 Hz), 6.73 (apparent d, 2H, J=8.5 Hz), 5.22 (apparent dd, 1H, J=4.9, 7.8 Hz), 3.15 (m, 2H), 2.65 (m, 2H), 2.51 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30–2.10 (m, 6H), 1.82 (m, 2H) 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][CH2:9][CH3:10]>>[CH2:7]([O:6][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCO
Reactant: O=CCCCO
Product: CCCCOC1CCCO1
Temperature: 22 °C
Reaction time: 17 h
Yield: 87.6 %

Procedure:
Aqueous 4-hydroxybutanal (502 g of 10.2 wt. % solution, 0.58 mol, 1.0 eq.), n-butanol (34.6 g, 0.47 mol, 0.80 eq.), hexanes (500 mL), and "Amberlyst-15" resin (product of Rohm and Haas Company, 2.3 g) are charged to a 2-L glass reaction vessel equipped with a magnetic stir bar. The two-phase mixture is stirred at ambient temperature (22° C.) for 17 h. The two liquid phases are separated from the ion-exchange resin. The hexane layer, which is separated from the aqueous phase and analyzed by gas chromatography (GC), contains 14.8 wt. % of 2-n-butoxytetrahydrofuran (59.4 g, 88.5% yield). Product identity is confirmed by infrared, 1H NMR, and 13C NMR spectroscopies. The aqueous phase contains 4.2% unreacted 4-hydroxybutanal.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:48]=[CH:47][C:40]([C:41]([NH:43][CH:44]2[CH2:46][CH2:45]2)=[O:42])=[CH:39][N:38]=1>>[CH:44]1([NH:43][C:41](=[O:42])[C:40]2[CH:47]=[CH:48][C:37]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[N:38][CH:39]=2)[CH2:46][CH2:45]1
Reactant: O=C(NC1CC1)c1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC3CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-N-cyclopropylnicotinamide following procedures analogous to those described in Example 486 Step 4. LC-MS Method tR=1.74 min, m/z=456.1; 1H NMR (CDCl3) 0.61 (m, 2H), 0.82 (m, 2H), 1.13 (s, 3H), 1.22 (s, 3H), 1.49 (d, 3H), 2.17 (m, 3H), 2.21 (m, 1H), 2.31 (m, 1H), 2.79 (m, 1H), 2.88 (m, 1H), 5.66 (m, 1H), 6.40 (s, 1H), 6.99 (d, 1H), 7.20-7.31 (m, 5H), 7.60 (d, 1H), 7.68 (d, 2H), 8.07 (d, 1H), 8.89 (s, 1H).
Reaction SMILES: [Li]C(C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>CCCCCCC.C1COCC1.O.CCOC(C)=O>[Cl:20][C:21]1[N:26]=[C:25]([C:16]2[S:15][C:14]([N:13]([C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=3)[CH3:19])=[N:18][CH:17]=2)[C:24]([F:27])=[CH:23][N:22]=1
Reactant: CN(c1ccc(F)cc1)c1nccs1
Reactant: Fc1cnc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)cc1)c1ncc(-c2nc(Cl)ncc2F)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
8.4 mL (13 mmol) of a 1.6 M solution of tBuLi in heptane was added to a rapidly stirred suspension of 2.5 g (12 mmol) of N-(4-fluorophenyl)-N-methylthiazol-2-amine in 50 mL of THF at −78° C. The solution was stirred for 1 min at −78° C. before 1.3 mL (13 mmol) of 2-chloro-5-fluoropyrimidine was added. The reaction solution was stirred for 1 h at −78° C., then quenched by addition of 2 mL of MeOH. Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.5 g, 24 mmol) was added and the reaction solution was stirred for 1 h and then 25 mL of 10% (w/v) aqueous NaOH was added. The reaction solution was warmed to rt and stirred 2 h, then poured into 500 mL of EtOAc and 200 mL of water, separated and the organic layer washed twice with saturated aqueous NaHCO3, once with brine, dried over MgSO4, filtered and concentrated. The residue was purified by C-18 prep MPLC to give the title compound. MS (M+H)+ 339.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][CH:6]=1.Br[CH2:21][CH2:22][O:23]C1CCCCO1>>[Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[N:5]([CH2:21][CH2:22][OH:23])[CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1

Procedure:
tert-butyl 4-formylpiperidine-1-carboxylate 4a was reacted with aqueous glyoxal in the presence of aqueous ammonium hydroxide in methanol to give tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate 4b, which was bromined to afford tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate 4c. 4c was alkylated with 2-(2-bromoethoxy)tetrahydro-2H-pyran, followed by removal of THP group under acidic condition to yield tert-butyl 4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate 4d. Suzuki coupling was performed with bromide intermediate 4d to afford 4e. 4e was reacted with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, followed by quenching with amine afforded 4f, which was treated with hydrogen chloride in methanol or trifloruoacetic acid in DCM to provide the amine intermediates 4g.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:28]#[C:27][CH2:26][CH2:25][OH:29])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(C#CCCO)c21

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.22 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)palladium(II) chloride (0.013 g), and 3-butyn-1-ol (0.040 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Hexanes are added to the reaction mixture and the resulting solid is filtered and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 1.5% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (2 L), 3% MeOH:CH2Cl2 (1 L)) affords the title compound as a light yellow solid (0.16 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([OH:18])=O)=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:18])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)O)cc1[N+](=O)[O-]
Product: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 1e from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[F:33][C:32]1[CH:31]=[CH:30][C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[CH:28][C:27]=1[CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:16])[CH2:26][CH2:25]1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 131 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.43 (dd, 1H, J=6.9, 2.5 Hz), 7.36–7.31 (m, 2H), 7.23–7.17 (m, 1H), 6.93 (t, 2H, J=8.4 Hz), 6.87 (t, 1H, J=8.9 Hz), 6.73–6.68 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.73–2.65 (m, 1 H), 2.45 (septet, 1H, J=6.7 Hz), 2.30–2.21 (m, 4H), 1.9–1.77 (m, 5H), 1.70–1.63 (m, 3H), 1.56–1.45 (m, 8H), 1.17 (d, 6H, J=6.7 Hz); ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[OH-:15].[Na+].Cl>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]=1[C:10]([OH:15])=[O:11])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A suspension of 57.6 g of 3-nitro-phthalimide (0.3 mol) in 672 g of water is cooled to 5° C. 80 g of 30% sodium hydroxide solution (0.6 mol, 2 equivalents) are added in the shortest possible time. After 2 hours at 5° C., the reaction mixture is added at 5° C. to 65 g of 32% hydrochloric acid solution (0.57 mol, 1.9 equivalents), which is diluted beforehand with 72 ml of water. The pH value is adjusted to 2-2.5 and the crude product which crystallises out is filtered off and washed twice with water. 6-Nitrophthalamic acid is obtained in a yield of 73%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([Si:10]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:11][CH:12]1[CH2:17][CH2:16][CH:15](C(C)C(OCC)=O)[CH2:14][CH2:13]1)([CH3:9])[CH3:8].C(OCC)(=O)C.N.[CH2:38]1C[O:41][CH2:40][CH2:39]1>>[CH:28]([Si:10]([CH:25]([CH3:27])[CH3:26])([CH:7]([CH3:9])[CH3:8])[O:11][CH:12]1[CH2:13][CH2:14][CH:15]([CH:40]([OH:41])[CH2:39][CH3:38])[CH2:16][CH2:17]1)([CH3:30])[CH3:29]
Reactant: CCOC(=O)C(C)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Reactant: C1CCOC1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Product: CCC(O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (2.7 g) was suspended in THF (200 ml). Ethyl 4-triisopropylsilyloxycyclohexylpropionate (s40) (21.3 g) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the mixture was stirred at the same temperature range for 2 hours. After the completion of reaction had been confirmed by means of GC analysis, ethyl acetate and a saturated aqueous solution of ammonia were added successively to the reaction mixture under ice-cooling, and the deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 4-triisopropylsilyloxycyclohexyl propanol (s41) (18.3 g). The yield based on the compound (s40) was 97.40.
Reaction SMILES: [OH:1][CH:2]([CH2:13][CH2:14][CH3:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:16](#[N:18])[CH3:17]>>[OH:9][CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:13][CH2:14][CH3:15])[CH:6]=1)[CH2:17][C:16]#[N:18]
Reactant: CC#N
Reactant: CCCC(O)COc1cccc(C=O)c1
Product: CCCC(O)COc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(2-hydroxypentyloxy)benzaldehyde gave 3-hydroxy-3-(3-(2-hydroxypentyloxy)phenyl)propanenitrile as a yellow oil. Yield (0.25 g, 12%): 1H NMR (400 MHz, CDCl3) δ 7.27-7.34 (m, 1H), 6.94-7.00 (m, 2H), 6.88 (dd, J=8.0, 2.0 Hz, 1H), 5.01 (t, J=5.6 Hz, 1H), 3.96-4.06 (m, 2H), 3.83 (dd, J=8.8, 7.6 Hz, 1H), 2.76 (d, J=6.0 Hz, 2H), 1.52-1.60 (m, 2H), 1.40-1.49 (m, 2H), 0.97 (t, J=6.8 Hz, 3H).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([N:21]([CH2:36][CH3:37])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)=[O:23])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([N:21]([CH:16]1[CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:38])=[O:5])[CH:20]=[CH:19][C:18]=2[CH2:17]1)[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=1)=[O:23])[CH3:37]
Reactant: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)O)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.2 %

Procedure:
To 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester (1.66 g; 3.0 mmol) dissolved in CH2Cl2 (15 mL) is added TFA (15 mL) and the reaction was stirred at RT for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 0.643 g (43%) of 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid as a white solid.