Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]2([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19]2)[N:3]=1.O.[NH2:29][NH2:30]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]4([CH2:21][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:20][CH2:19]4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NC3(Cc4ccccc4)CC3)nc(N)n2)cc1F
Solvent: CCO
Solvent: O
Product: Nc1nc(NC2(Cc3ccccc3)CC2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(2-amino-6-{[1-(phenylmethyl)cyclopropyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (124 mg, 0.34 mmol) and hydrazine hydrate (99%, 2 mL) in ethanol (10 mL) was stirred and heated at 120° C. for 1 hour in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The resulting solids were purified by reverse phase chromatography with CH3CN in water (0.08% ammonium hydrogen carbonate) (gradient: 35% to 45% in 6 min: flowrate: 30 mL/min), to afford the title compound (30 mg) as a white solid. LC-MS (ES) m/z=372 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.78 (d, 4H), 2.93 (s, 2H), 5.37 (s, 2H), 5.97 (s, 2H), 6.32 (s, 1H), 6.90 (s, 1H), 7.18 (d, 3H), 7.27 (t, 2H), 7.40 (s, 1H), 7.69 (d, 1H), 7.81 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: C([O:8][CH2:9][CH:10]([C@H:12]1[CH2:16][O:15][C@@H:14]([CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:13]1)[OH:11])C1C=CC=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[Si:19]([O:18][CH2:17][C@H:14]1[O:13][C@@H:12]([CH:10]([OH:11])[CH2:9][OH:8])[CH2:16][O:15]1)([C:32]([CH3:34])([CH3:35])[CH3:33])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1OC[C@H](C(O)COCc2ccccc2)O1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC[C@@H]1OC[C@H](C(O)CO)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of (-)-(2R,4R)-4-(2-benzoxy-1-hydroxyethyl)-2-(t-butyldiphenylsilyloxy-methyl)-dioxolane (2.52 g, 5.0 mmole) in methanol (40 ml) was added a 0.078 M solution of sodium methoxide (7.3 ml) in methanol. The mixture stirred at room temperature for two hours. The mixture was neutralized with acetic acid and concentrated. The residue was then portioned between ethyl acetate and water, and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with a saturated NaHCO3 solution and then water, and then dried, evaporated, and purified by column chromatography over silica gel to yield 6 (1.9 g, 95%) as colorless oil: [α]25D-2° (C 0.25, MeOH); 1H NMR (DMSO-d6) δ 1.00 (s, 9H, t-Bu), 3.40-3.52 (m, 3H, CH2OH and CHOH), 3.64 (d, J=3.7 Hx, 2H, CH2OTBDPS), 3.82-3.95 (m, 3H, 4.5-H), 4.49 (t, J-5.3 Hz, 1H, pri OH, D2O exchangeable), 4.82 (d, J=5.1 Hz, 1H, sec OH, D2O exchangeable), 5.01 (t, J-3.7 Hz, 1H, 2-H), 7.36-7.71 (m, 10H, Ar-H); Anal. Calcd for C22H33H30O5Si: C, 65.63; H, 7.53. Found: C, 65.72; H, 7.52.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:34][O:35][CH3:36])=[C:13]([CH:32]=O)[N:14]=[CH:15][C:16]=1[N:17]2[S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:38][OH:39]>C(O)C>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:34][O:35][CH3:36])=[C:13]([CH:32]=[N:38][OH:39])[N:14]=[CH:15][C:16]=1[N:17]2[S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: COCc1c(C=O)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CCO
Product: COCc1c(C=NO)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1

Procedure:
500 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carbaldehyde is heated in 15 ml of ethanol to 70° C., combined with 84 mg of hydroxylamine hydrochloride in 10 ml of ethanol and heated for 1.5 hours to 70° C. Then the mixture is concentrated to 5 ml, poured on 40 ml of water, and suctioned off. The residue (450 mg) is utilized after drying in the subsequent stage without further purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[CH2:20][CH:19]4[C:21]4[O:22][C:23]([NH:26][C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=5)=[N:24][N:25]=4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:37])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:33]([F:34])([F:36])[C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23]2[O:22][C:21]([C@@H:19]3[CH2:20][C@H:18]3[C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[NH:8][C:9](=[O:37])[CH:10]=[CH:11]4)=[N:25][N:24]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2c(=O)ccc3cc(C4CC4c4nnc(Nc5ccc(C(F)(F)F)cc5)o4)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccc2cc([C@@H]3C[C@H]3c3nnc(Nc4ccc(C(F)(F)F)cc4)o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-6-(2-(5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-oxadiazol-2-yl)cyclopropyl)quinolin-2(1H)-one (35 mg, 0.065 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.49 mmol) and stirred at room temperature overnight. The solvent was concentrated to give a crude product, purified by preparative HPLC on a Sunfire C18 column (150×19, 5μ) using a gradient of 0-100% ACN in 0.1% TFA to give trans-6-(2-(5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-oxadiazol-2-yl)cyclopropyl)quinolin-2(1H)-one. 1H NMR 400 MHz, MeOD: δ 1.65-1.79 (m, 2H), 2.43-2.47 (m, 1H), 2.70-2.75 (m, 1H), 6.64 (d, J=9.20 Hz, 1H), 7.35 (d, J=8.80 Hz, 1H), 7.47 (dd, J=2.00, 8.60 Hz, 1H), 7.57 (d, J=1.60 Hz, 1H), 7.68 (dd, J=8.80, 23.20 Hz, 4H), 7.97 (d, J=9.20 Hz, 1H). LCMS, RT 1.869 min; LCMS (ES-API), m/z 412.11.
Reaction SMILES: Cl[CH2:2][Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[Si:13]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])(Cl)Cl>C1COCC1>[Si:3]([CH2:2][Si:13]([CH2:2][Si:3]([O:4][CH2:5][CH3:6])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CCO[Si](CCl)(OCC)OCC
Reactant: CCO[Si](Cl)(Cl)OCC
Solvent: C1CCOC1
Product: CCO[Si](C[Si](OCC)(OCC)OCC)(C[Si](OCC)(OCC)OCC)OCC
Temperature: 25 °C
Yield: 90 %

Procedure:
2 molar equivalents of ClCH2Si(OEt)3, 2 molar equivalents of Mg (sanded ribbon), and molar 1 equivalent of SiCl2(OEt)2 were added in flask with THF (Na treated) under N2. The mixture was stirred at room temperature until Mg disappeared. THF was removed by distillation. Pentane was added to extract the intermediate and then filtered to separate solid. After distillation of pentane, >90% yield crude (EtO)3Si—CH2—Si(OEt)2-CH2—Si(OEt)3 was obtained. (EtO)3Si—CH2—Si(OEt)2-CH2—Si(OEt)3 was directly reduced without further purification by 3 molar equivalents (based on the amount of (EtO)3Si—CH2—Si(OEt)2-CH2—Si(OEt)3) of LiAlH4 in ether in ice bath under N2. The mixture was stirred for ˜6 hours at room temperature. The volatiles were separated from solid by-products and LiAlH4 by vacuum transfer, and ether was removed from the collected volatives by distillation using a 55° C. bath. The final distillation give pure trisilapentane (TSP) as 70% overall yield. The pure TSP was analysed by GC as shown in FIG. 2, which indicates no undesired by-products remain. TSP: 1H NMR (C6D6): δ 3.95 (p, 2H, SiH2), 3.67 (t, 6H, SiH3), −0.40 (m, 4H, CH2). MS, m/z: 120 [M+].
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[O:31])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCn1ncc2cc(N)ccc21
Solvent: C1CCOC1
Product: CN(C)CCn1ncc2cc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)ccc21
Temperature: 50 °C

Procedure:
A mixture of 1-(2-dimethylamino-ethyl)-1H-indazol-5-ylamine (42 mg, 0.17 mmol), 4-phenoxyphenyl isocyanate (36 mg, 0.17 mmol) in 2 mL of THF was heated to 50° C. for 6 hours, cool to room temperature and concentrated under reduced pressure. The residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.85 (s, 6H), 3.63 (t, J=6.40, 2H), 4.77 (t, J=6.40, 2H), 7.09 (m, 2H), 6.97 (m, 4H), 7.36 (m, 2H), 7.47 (m, 1H), 7.57 (m, 2H), 7.67 (m, 1H), 7.97 (s, 1H), 8.10 (s, 1H), 8.98 (s, 1H); MS (DCI/NH3) m/z 416 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC1CCCCC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(Oc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, cyclohexanol and DBU in dioxane. EI-MS m/e (%): 339 (M{81Br}+, 15), 337 (M{79Br}+, 16), 257 ([M—C6H10]+, 97), 255 ([M—C6H]+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[N:25][C:26]([Cl:32])=[CH:27][CH:28]=2)[N:23]=1>>[Cl:32][C:26]1[N:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([N:13]3[CH:12]([O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:21])=[N:23]2)=[CH:28][CH:27]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: CN1CCC(OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 19.7 %

Procedure:
Working in a manner similar to that described in Example 6, but starting with 1-methyl-4-piperidinol (4.3 g), sodium hydride (0.9 g) and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (12.4 g), and heating the reaction mixture for 90 minutes under reflux, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(1-methyl-4-piperidyloxy)-1-isoindolinone (3 g), m.p. 204° C., is obtained after recrystallization in ethanol.
Reaction SMILES: [CH3:1][CH:2]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:3][CH2:4]OC1C=CC=CC=1.[BrH:17]>C(Cl)(Cl)Cl>[BrH:17].[CH3:1][CH:2]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:3][CH2:4][Br:17]
Reactant: CCN(CC)C(C)CCOc1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(C)CCBr
Yield: 78 %

Procedure:
5 g of the 1-methyl-3-phenoxypropyldiethylamine was reacted with 30 ml of 40% hydrobromic acid at 150° C. for 7 hours with stirring. The reaction solution was cooled and added with 20 ml of chloroform, and then the hydrobromic acid layer was separated from the chloroform layer. The hydrobromic acid was removed under reduced pressure and the residue was recrystallized from 5 ml of ethyl alcohol to give 4.88 g of 1-methyl-3-bromopropyldiethylamine hydrobromide in a yield of 78%.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31](O)=[O:32])[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:67]1([S:79]([NH2:82])(=[O:81])=[O:80])[CH2:72][CH2:71][CH:70]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[C:31](=[O:32])[N:76]3[CH2:75][CH2:74][CH:73]([CH:70]4[CH2:71][CH2:72][N:67]([S:79](=[O:81])(=[O:80])[NH2:82])[CH2:68][CH2:69]4)[CH2:78][CH2:77]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Reactant: NS(=O)(=O)N1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(S(N)(=O)=O)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 73 mg (0.14 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 51 mg (0.16 mmol) TBTU, 42 μL (0.3 mmol) triethylamine and 41 mg (0.14 mmol) [4,4′]bipiperidinyl-1-sulphonic acid amide (used as the hydrochloride salt) in 1.8 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH:22]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=2)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH2:22][N:29]3[CH2:34][CH2:33][CH:32]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH2:31][CH2:30]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CC=O)CCCCC2)c1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(Nc4ccc(C)cn4)CC3)CCCCC2)c1
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
1,3-Diacetoxymethyl-5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzene (synthesized in Example 32) (215 mg) and 2-(piperidin-4-ylamino)-5-methylpyridine (synthesized in Preparation Example 4-3) (126 mg) were dissolved in 1,2-dichloroethane (5 mL). To this was added acetic acid (0.04 mL) at room temperature. The solution was stirred for 45 minutes. Sodium triacetoxyborohydride (295 mg) was added to the solution at room temperature and it was stirred for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the solution and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give the title compound (258 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=O)=[CH:22]3)[CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:22]3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of oxindole (27 mg, 0.2 mmol), 5-(3-pyrrolidin-1-yl-propyl)-1H-indole-2-carbaldehyde (51 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol/ethyl acetate and dried to give 55 mg (74%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH:24]([C@H:26]([C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1)[CH3:27])[NH2:25].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:24]([C@H:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:25]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)NN)cc1
Reactant: O=C(C#Cc1cc(Cl)cc(Cl)c1)c1cnc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3ccccc3c2)cc1

Procedure:
To a solution of the intermediate from step C (152 mg, 0.46 mmol) in DMF (5 mL) was added the ethyl 4-[(1S)-1-hydrazinoethyl]benzoate hydrochloride (126 mg, 0.51 mmol) and triethyl amine (86 μL, 0.61 mmol). After stirring, the reaction mixture at room temperature for 2 hours it was concentrated in vacuo. The residue was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 10% ethyl acetate-hexanes. This material was then re-purified with 75% hexanes-dichloromethane to give the desired compound as the major product. 1H NMR (CDCl3, 500 MHz): 8.84 (d, J=2.0 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.99 (d, J=2.1 Hz, 1H), 7.83 (d, J=1.8 Hz, 2H), 7.78 (m, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.34 (t, J=1.8 Hz, 1H), 7.28 (d, J=8.2 Hz, 2H), 6.77 (s, 1H), 5.58 (q, J=7.1 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.02 (d, J=7.1 Hz, 3H), 1.4 (t, J=7.0 Hz, 3H). LC-MS: 4.64 min; (M+H)=516.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([NH:8][C:9](=[O:13])/[CH:10]=N\O)[CH:7]=1.[OH:15]S(O)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[C:7]=1[C:10](=[O:15])[C:9](=[O:13])[NH:8]2
Reactant: Cc1ccc(F)cc1NC(=O)/C=N\O
Reactant: O=S(=O)(O)O
Product: Cc1ccc(F)c2c1NC(=O)C2=O
Temperature: 60 °C

Procedure:
(Z)—N-(5-Fluoro-2-methylphenyl)-2-(hydroxyimino)acetamide (7.22, 37 mmol) was dissolved in neat H2SO4 (50 ml) and heated at 60° C. for 1 h. The resulting solid was collected by filtration and washed with water to yield the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.35 (bs, 1H), 7.45 (m, 1H), 6.73 (m, 1H), 2.25 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][S:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[CH3:25][S:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: CSc1cccc(N=C=O)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-methylthiophenyl isocyanate (0.168 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 168 mg (50.3%) of the desired product as a solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20]>O>[CH:1]([NH:4][C:6]1[C:14]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Solvent: O
Product: CC(C)Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Isopropylamine (120 ml) and water (8 ml) were added to 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g), while cooling. Then the reaction mixture was stirred for 5 days at room temperature. After evaporation in vacuo, the residue was triturated with 4N hydrochloric acid, after which the resulting 4-isopropylamino-3-nitro-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the acid was obtained with a melting point of 206°C (decomp.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](O)=[O:22])=[CH:15][CH:14]=1.S(Cl)([Cl:31])=O>ClCCl.CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([Cl:31])=[O:22])=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
To (0.05 mol) of 3-(4-(2-quinolinylmethyloxy)benzyl)benzoic acid in dichloromethane solution (500 ml) and chilled in an ice bath is added thionyl chloride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzoyl choride.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1C)=[O:4].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4]
Reactant: NCCO
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NCCO)s1
Yield: 63 %

Procedure:
As described for example 66, 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (55 mg, 0.17 mmol) was converted, using ethanolamine instead of rac-2-amino-1-propanol, to the title compound (34 mg, 63%) which was obtained as a light yellow solid. MS: m/e=356.2 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12)([CH3:3])[CH3:2].[CH2:26]1[O:28][CH2:27]1>C(O)C>[CH:1]([N:4]([CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12)[CH2:26][CH2:27][OH:28])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Reactant: C1CO1
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)N(CCO)C(C)C)=C21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of 5 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one and 14.75 ml of liquified ethylene oxide in 100 ml of absolute ethanol is stirred in a sealed pressure tube at room temperature for two days. The reaction mixture is recharged with an additional 14.75 ml portion of ethylene oxide and stirred for four additional days at room temperature. It is evaporated, the residue slurried in diethyl ether, collected by filtration and recrystallized from ethyl acetate to yield the 1-[2-(N-isopropyl-N-2-hydroxyethylamino)-propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate melting at 147°-149°.