Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[CH2:13]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH:24]([CH3:28])[CH:25](O)[OH:26])[CH2:20][CH2:19]1)[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>O>[F:1][C:2]([F:11])([F:12])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH:9]2[O:26][CH2:25][CH:24]([C@H:21]3[CH2:20][CH2:19][C@H:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)[CH2:28][O:10]2)[CH2:7][CH2:8]1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCCCC[C@H]1CC[C@H](C(C)C(O)O)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](C2COC([C@H]3CC[C@H](C(F)(F)F)CC3)OC2)CC1

Procedure:
A mixture of 0.02 mol of tras-4-trifluoromethyl-1-formylcyclohexane (prepared as in Example 3), 0.02 mol of 2-(trans-4-pentylcyclohexyl)propanediol (prepared as in DE 3,227,916), 30 ml of toluene and 0.5 g of pTSOH is heated for 6 hours on a water separator. The product is obtained after customary work-up and crystallization.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[CH:54][C:55]4[N:56]([CH2:66][CH2:67][F:68])[C:57](=[O:65])[N:58]([CH2:62][CH2:63][F:64])[CH2:59][C:60]=4[N:61]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[CH:54][C:55]4[N:56]([CH2:66][CH2:67][F:68])[C:57](=[O:65])[N:58]([CH2:62][CH2:63][F:64])[CH2:59][C:60]=4[N:61]=3)=[CH:48][CH:47]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)N(CCF)C4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)N(CCF)C4)cc2)CCC1
Yield: 36 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1,3-bis(2-fluoroethyl)-2-oxo-7-phenyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.03 mmol) was reacted to afford the title compound (5 mg, 27%). LCMS (Method D): RT=0.872 min, M-NH2=446. 1H NMR (500 MHz, MeOD): 7.52 (1H, s), 7.45-7.39 (4H, m), 7.32-7.30 (3H, m), 7.24-7.22 (2H, m), 4.81-4.77 (4H, m), 4.68 (2H, dt), 4.28 (2H, dt), 3.83 (2H, dt), 2.81-2.75 (2H, m), 2.63-2.57 (2H, m), 2.26-2.24 (1H, m), 1.99-1.97 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:20][CH2:21][CH3:22])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18][NH2:19])[CH2:5]1)[CH3:2].C(N(CC)CC)C.C[O:31][C:32](=O)[C:33]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:41]Cl>C(#N)C>[CH3:40][O:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:33]=1[C:32](=[O:31])[N:19]([CH2:18][C@H:6]1[CH2:5][C:4]([O:3][CH2:1][CH3:2])([O:20][CH2:21][CH3:22])[CH2:9][CH2:8][N:7]1[C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[CH2:41]2
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN)C1
Reactant: COC(=O)c1c(CCl)cccc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2Cc3cccc(OC)c3C2=O)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
4,4-Diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-aminomethyl-piperidine (2.25 g, 7.37 mmol), and triethyl amine (1.49 g, 14.7 mmol) in acetonitrile (50 ml) was heated to 60° C. before 2-chlormethyl-6-methoxy-benzoic acid methyl ester (1.58 g, 7.37 mmol) in acetonitrile (25 ml) was added over the course of 1.5 hour. After addition the reaction mixture was stirred overnight at 60° C. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (50 ml) and washed with saturated sodium bicarbonate. After drying (MgSO4), filtration and evaporation of the solvent in vacuo the residue was subjected to flash column chromatography (SiO2, ethyl acetate-light petrol ether (1:1)) to give 2.3 g (69%) of 2-(R)-(7-methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-piperidine.
Reaction SMILES: C[Si](Cl)(C)C.[CH:6]1(/[CH:11]=[C:12](\I)/[C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:38]1[CH:39]=[CH:40][C:41]([S:44][CH3:45])=[N:42][CH:43]=1>C1COCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:6]1([CH:11]=[C:12]([C:38]2[CH:43]=[N:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CSc1ccc(Br)cn1
Reactant: COC(=O)/C(I)=C/C1CCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(=CC1CCCC1)c1ccc(SC)nc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
DBE (345 μL, 4.0 mmol) was added to a suspension of Zn dust (2.62 g, 40.0 mmol) in anhydrous THF (4 mL). The mixture was heated to boiling, then allowed to cool down to 20° C. This process was repeated three times, then the mixture was stirred at 20° C. for 2 h, before being treated with TMSCl (380 μL, 3.0 mmol). Stirring was continued for 1.5 h, then a solution of (Z)-methyl 3-cyclopentyl-2-iodoacrylate (2.52 g, 9.0 mmol) in anhydrous THF (8 mL) was added over 3 min. The mixture was stirred at 40° C. for 2 h, before being stirred at 20° C. for 16 h, and finally allowed to stand for 4 h. In a separate reaction vessel, a solution of PPh3 (315 mg, 1.2 mmol) and Pd2(dba)3 (150 mg, 0.5 mmol) in anhydrous THF (15 mL) was stirred for 2 h at 20° C., before being treated with a solution of 5-bromo-2-methylsulfanylpyridine (2.76 g, 13.5 mmol) in anhydrous THF (10 mL). The solution of the freshly prepared organozinc compound was then added via cannula, and the mixture was stirred at 40° C. for 68 h. Solvent evaporation and column chromatography (4:1 IH-Et2O) yielded methyl 3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylate: m/z (ES+)=278.1 [M+H]+. Step 2: A solution of this compound (1.12 g, 4.0 mmol) in MeOH (5.5 mL) was treated with 1M NaOH (8.9 mL, 8.9 mmol). The mixture was heated at 65° C. for 3 h, before being stirred at 20° C. for 16 h. The MeOH was removed under reduced pressure, then H2O (10 mL) and 1M NaOH (10 mL) were added. The resulting mixture was washed with Et2O (25 mL), before being acidified with 2M HCl to adjust the pH to 1. The suspension produced was extracted with EtOAc (2×50 mL), then the extracts were washed with brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and recrystallisation (EtOAc-IH) furnished the title compound: m/z (ES+)=264.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.Cl>CO>[NH:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:27])[F:28])=[CH:5][CH:6]=2)=[O:26])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Yield: 89 %

Procedure:
Intermediate 41 (2.02 g, 5.0 mmol) was treated with 1M HCl in methanol (35 mL) and refluxed for 3 hours. The solvent was evaporated and the residue diluted with 1N NaOH. The resulting precipitate was removed by filtration and further dried under high vacuum to give intermediate 42 (1.35 g, 89%) as a white solid: Mp 169-173° C. 1H NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.46 (d, J=9.0 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.15 (d, J=7.7 Hz, 1H), 3.55-3.45 (m, 1H), 2.89 (td, J=12.8, 3.5 Hz, 2H), 2.49-2.45 (m, 2H), 2.13 (s, 1H), 1.74 (dd, J=12.4, 2.4 Hz, 2H), 1.21 (dq, J=11.7, 3.7 Hz, 2H). HRMS calculated for C13H16F3N3O2−H+ 302.1117. found (ESI(−), [M−H]) 302.1114.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C(=O)c2ccc(C)cc2)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56 mg), 2-hydroxy-4-methoxy-4′-methylbenzophenone (242 mg), and 4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-hexane to give the title compound (46 mg, yield 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1C(=O)c1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(F)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-fluoro-phenyl)-phenyl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.64 (s, 3H), 6.62 (d, 2H, J=9.2 Hz), 7.02 (m, 1H), 7.25 (m, 1H), 7.31 (m, 2H), 7.37 (m, 2H), 7.48 (m, 2H), 7.56 (m, 1H), 7.79 (q, 1H, J=9.2 Hz, 4.8 Hz), 9.34 (s, 1H). MS: m/z 386.0 (M++1).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][C:18]#[C:19][CH2:20][CH2:21][CH3:22])[CH:12]=O.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CCCC#COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 75.3 %

Procedure:
Piperidine (0.45 mL, 4.6 mmol) was added to a suspension of 3-methoxy-4-(pent-1-ynyloxy)benzaldehyde (1.0 g, 4.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.93 g, 4.2 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-methoxy-4-(pent-4-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.2 g, 75%) as a pale yellow crystalline solid; mp 166.5-167.5° C.; δH (400 MHz, DMSO-d6) 1.89 (p, J=7.6 Hz, 2H, CH2), 2.32 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.81 (t, J=2.4 Hz, 1H, CCH), 3.84 (s, 3H, OCH3), 4.06 (t, J=7.6 Hz, 2H, OCH2), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.17 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (dd, J5′,6′=8.0, J2′,6′=2.0 Hz, 1H, H6′), 7.37 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 14.5, 27.7, 55.7, 66.7, 71.7, 83.6, 110.7, 112.7, 116.6, 120.0, 120.3, 122.6, 122.7, 127.4, 131.1, 134.0, 141.1, 141.6, 149.2, 149.8, 164.1, 169.4; HRMS (ESI) calculated for C22H21NO5 [M+H]+ 380.1492. found 380.1493; vmax 755, 1257, 1506, 1584, 1657, 2929, 3266, 3519 cm−1.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12]>[OH-].[Na+]>[CH3:10][Si:11]([CH2:14][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 10 °C
Yield: 81.5 %

Procedure:
A mixture of 264 mL (2.42 mol) of benzylamine and 97.7 g. (0.796 mol) of chloromethyltrimethylsilane was heated to 200° C. for 2.5 h then cooled to 10° C. A 0.1M sodium hydroxide solution (400 mL) was added and the product was extracted with 3×200 mL of diethyl ether. The combined organic phase was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled at 115°-125° C. and 5 mm of Hg to give 125.4 g (81% yield) of N-trimethylsilylmethyl benzylamine as a clear liquid; 1H NMR (CDCl3) δ:0.0 (s, 9H), 1.1 (br s, 1H), 2.01 (s, 2H), 3.76 (s, 2H), 7.1-7.3 (m, 5H).
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O.CN.[C:30]([BH3-])#[N:31].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:30][NH:31][CH2:1][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(C=O)c(-c2ccccc2)c1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1ccc(Oc2cc(C(F)(F)F)ccc2C#N)cc1-c1ccccc1
Yield: 53.7 %

Procedure:
2-(4-Formyl-3-phenyl-phenoxy)-4-trifluoromethyl-benzonitrile (0.117 g, 0.35 mmol), methylamine (2M in methanol, 0.233 mL, 1.05 mmol) and sodium cyanoborohydride (0.025 g, 0.39 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. Fumaric acid (0.032 g, 0.28 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 2-(4-methylaminomethyl-3-phenyl-phenoxy)-4-trifluoromethyl-benzonitrile fumarate (75 mg, 61%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O-:3])=[O:2].[C:22]1(=[O:26])[CH2:25][CH2:24]C1.C([BH3-])#N.[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:25]2[CH2:22][O:26][CH2:24]2)[CH2:16][CH2:17]1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(OCC2CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(OCC2CCN(C3COC3)CC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a suspension of 3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide (0.100 g) and cyclobutanone (0.030 g) in methanol (1 mL) was added sodium cyanoborohydride (0.027 g). After stirring overnight, the reaction was quenched with saturated NaHCO3 (5 mL) and extracted into dichloromethane (2×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: N#N.[C:3]([NH:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([CH3:6])([CH3:5])[CH3:4].C([Li])(CC)C.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>O.C1COCC1>[C:3]([N:7]1[CH:28]([OH:29])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[C:8]1=[O:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Temperature: -78 °C
Yield: 87.6 %

Procedure:
In a 1 L three-necked flask fitted with an addition funnel with line to a bubbler, and a nitrogen inlet, that was purged with N2, N,4-di-tert-butylbenzamide (5 g, 21.4 mmol, Eq: 1.00) was combined with THF (200 ml) to give a light yellow solution. The reaction was cooled to −78° C. The sec-butyllithium in cyclohexanes (31.4 ml of 1.4 M, 43.9 mmol, Eq: 2.05) was added dropwise slowly and with a stream of N2. A yellow solution resulted. The reaction mixture was warmed to −15° C. for 1 h. A pale yellow suspension resulted. The reaction mixture was cooled back down to −78° C. Dry DMF (3.13 g, 3.32 ml, 42.9 mmol, Eq: 2) was added dropwise. The reaction mixture was allowed to warm to room temperature. 30 mL of saturated NH4Cl was added slowly at 0° C. The reaction mixture was poured into 150 mL H2O and extracted with EtOAc (3×250 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 40% EtOAc in hexanes to afford the desired product (4.9 g, 88% yield). (M+H)+=262 m/e.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11](=[O:38])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])C)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[CH3:15][CH:14]([CH3:16])[C@H:13]([NH:12][C:11](=[O:38])[C@@H:9]([NH:7][CH3:6])[CH3:10])[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:18]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1CNC(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((S)-1-{(S)-1-[(S)-2-(benzoylamino-methyl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl]-2-methyl-propylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (30 mg, 0.056 mmol) in dioxane (0.5 mL) was added dropwise 4 M HCl in dioxane (0.3 mL) at 0° C. The reaction mixture was stirred for 2 h at rt and then the solvent removed in vacuo. Trituration of the residue with hexane gave N—{(S)-1-[(S)-3-Methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl}-benzamide, hydrochloride as an off white solid (25 mg), m/z=438 (M+H).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C:4]([CH3:14])([CH3:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>O1CCOCC1>[C:2]([CH2:3][C:4]([CH3:14])([CH3:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:1]
Reactant: CC(C)(CC(N)=O)CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(CC#N)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Tert-butyl 5-amino-3,3-dimethyl-5-oxopentanoate (3.17 g, 14.7 mmol) was dissolved in dioxane (32 mL) containing pyridine (8 mL) and the solution was cooled to 0° C. Trifluoroacetic anhydride was added dropwise over 25 minutes keeping the temperature between 0-5° C. The mixture was stirred at 0° C. for one hour and then at room temperature overnight. A few chips of ice were added, followed by ethyl acetate (250 mL). The ethyl acetate was washed with brine, dried (Na2SO4) and removed under reduced pressure. The residue was purified by flash chromatography 7:3 (hexane:ethyl acetate) to give 2.1 g (72%) of the desired product. 1H NMR (CDCl3) 2.44 (s, 2H), 2.21 (s, 2H), 1.39 (s, 9H), 1.10 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]2[C:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[CH2:23][CH:24]=1)#[N:2].[OH-].[NH4+]>C(O)(=O)C.O=[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[CH2:23][CH2:24]1
Reactant: N#Cc1ccc2c(c1)c(C1=CCN(CCN3CCNC3=O)CC1)cn2-c1ccc(F)cc1
Agent: O=[Pt]=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCc1ccc2c(c1)c(C1CCN(CCN3CCNC3=O)CC1)cn2-c1ccc(F)cc1

Procedure:
5-Cyano-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-1,2,3,6-tetrahydropyridin4-yl]-1H-indole (Perregaard, J.; Bges, K. P.; Hyttel, J.; Sánches, C.: J Med. Chem., 1992, 35, 1092-1101) (4.6 g) was hydrogenated with PtO2 in acetic acid at 3 ATO for 5 h. Ice and ammonium hydroxide was added to pH 9 and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, dried over MgSO4 and the solvent was removed in vacuo. The title compound was purified by preparative HPLC (ethanol/NH4OH 100/4). Yield 0.9 g, mp. 171-175° C. (diethyl ether). 1H-NMR (CDCl3) 1.85 (d, 2H), 2.10 (d, 2H), 2.25 (td, 2H), 2.60 (t, 2H), 2.90 (tt, 1H), 3.10 (d, 2H), 3.4 (q, 4H), 3.6 (q, 2H), 3.95 (s, 2H), 4.70 (s, broad, 1H), 7.00 (s, 1H), 7.10-7.25 (m, 3H), 7.30-7-50 (m, 3H), 7.60 (s, 1H). Analysis: Calc (corrected for 1% water): C: 68.22, H: 7.01, N: 15.92 Found: C: 67.51, H: 6.90, N: 15.37
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[NH:23][C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[N:23]([CH2:30][CH2:31][CH2:32][CH3:33])[C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCBr
Reactant: O=C1CN2Cc3cc(OCCCCCCn4ccnc4)ccc3N=C2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CN2Cc3cc(OCCCCCCn4ccnc4)ccc3N=C21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(6-(N-imidazolyl)hexyl)oxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one in dry dimethylformamide is added sodium hydride (1.05 equivalents). The mixture is stirred at 60° C. for 30 minutes to give a homogeneous solution. 1-bromobutane (1.1 equivalents) is added via a syringe after which the mixture is stirred at 60° C. for 2 hours. The solvent is evaporated and the residue taken up in ethyl acetate which is washed with saturated brine, dried and filtered. Evaporation of the solvent affords 7-(6-(N-imidazolyl)hexyl)oxy-1-butyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:45]([NH:47][NH2:48])=[O:46]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([NH:48][NH:47][CH:45]=[O:46])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)O)c2ccccc2)CC1
Reactant: NNC=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.4 %

Procedure:
A mixture of 4-(1-phenyl-1-carboxy-methylene)piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 3.31 mmol), EDCI (0.888 g, 4.63 mmol) and HOBt (0.626 g, 4.63 mmol) in DMF (4 mL) was stirred for 30 min at room temperature and then formic hydrazide (3.97 g, 66.2 mmol) was added. Stirring was continued for 1 h and then the mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed (H2O ×3, brine), dried (Na2SO4) and evaporated to give the title compound (1.48 g, 97%) as a colorless oil: