Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([NH2:29])[CH:26]1[CH2:28][CH2:27]1)[CH3:21]>CO>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([CH:26]1[CH2:28][CH2:27]1)[NH:29][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC(N)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)CC(NCc1ccc(F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.7 %

Procedure:
4-Fluorobenzaldehyde (0.565 mL, 5.27 mmol), sodium acetate (0.864 g, 10.5 mmol), powdered/activated 4 Å molecular sieves (1.0 g) and sodium cyanoborohydride (0.662 g, 10.5 mmol) were added sequentially to a solution of racemic 3-amino-3-cyclopropyl-propionic acid ethyl ester hydrochloride (1.02 g, 5.27 mmol) in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 17 h, and then was filtered through Celite. The Celite was washed with methanol (2×30 mL) and the combined filtrate and washings were partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-cyclopropyl-3-(4-fluoro-benzylamino)-propionic acid ethyl ester (0.75 g, 2.83 mmol, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.00-0.06 (1H, m), 0.16-0.22 (1H, m), 0.36-0.43 (1H, m), 0.50-0.57 (1H, m), 0.75-0.84 (1H, m), 1.18 (3H, t, J=7.0 Hz), 2.17-2.23 (1H, m), 2.53 (2H, d, J=6.1 Hz), 3.74 (1H, d, J=12.4 Hz), 3.87 (1H, d, J=12.3 Hz), 4.05 (2H, q, J=7.0 Hz), 6.88-6.96 (2H, m), 7.21-7.25 (2H, m).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([Si:16]([CH:29]=[CH2:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:15]>>[C:8]1([P:7]([CH2:30][CH2:29][Si:16]([CH2:14][CH2:15][P:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](C=C)(c1ccccc1)c1ccccc1
Product: c1ccc(P(CC[Si](CCP(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
About 2 moles of diphenyl phosphine were added sequentially to one mole of divinyl diphenyl silane to yield mostly the desired diadduct which crystallized on standing; recrystallization from heptane provided the pure product.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[C:13](=[O:30])[CH2:12]1)=O)C1C=CC=CC=1.[ClH:31]>C(OCC)(=O)C.CO.[Pd]>[ClH:31].[ClH:31].[ClH:31].[N:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][CH:18]([NH:17][N:14]3[CH2:15][CH2:16][NH:11][CH2:12][C:13]3=[O:30])[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(NC2CCN(c3ccncc3)CC2)C(=O)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CNCCN1NC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 4-benzyloxycarbonyl-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (25.29 g) and an a 4N solution of hydrochloric acid in ethyl acetate (15.5 ml) in methanol (300 ml) was combined with 10% Pd/C (50% hydrated, 5.00 g) and stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off, and the reaction mixture was concentrated. The residue was dissolved in ethanol (300 ml), and combined with a 4N solution of hydrochloric acid in ethyl acetate (31 ml). The crystals precipitated were collected by filtration and dried to obtain 1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone trihydrochloride (20.16 g) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(C1C=CC([N+]([O-])=O)=CC=1OCCN1CCCCC1)(C)(C)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[C:8]([CH:9]=1)[O:10][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Reactant: ClCCN1CCCC1
Agent: CC(C)(C)c1ccc([N+](=O)[O-])cc1OCCN1CCCCC1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(OCCN2CCCC2)c1

Procedure:
1-[2-(5-Nitro-2-trifluoromethylphenoxy)ethyl]-pyrrolidine was prepared from 5-nitro-2-trifluoromethyl-phenol and 1-(2-chloroethyl)pyrrolidine by a procedure similar to that described for 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C(N(CC)CC)C.Cl[Si:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][Si:18](Cl)([CH3:20])[CH3:19]>ClCCl>[CH3:5][C:2]([N:1]1[Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][Si:15]1([CH3:23])[CH3:22])([CH3:6])[C:3]#[CH:4]
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: C#CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: 15 °C
Reaction time: 3 h

Procedure:
3-Amino-3-methylbutyne (commercially available as 90% aqueous solution; 16.6 g) was dissolved in dichloromethane (150 ml), dried over sodium sulphate and filtered to give a solution containing 14.9 g of amine. To the stirred solution of amine under an atmosphere of nitrogen at ambient temperature was added dry triethylamine (48.4 ml). 1,2-Bis-(chlorodimethylsilyl)ethane (38.98 g) in dichloromethane (100 ml) was then added dropwise, maintaining the reaction temperature at 15° C. by cooling. The mixture was stirred for 3 hours, the colourless solid, which had formed during the reaction, was filtered from solution and the filtrate was evaporated under reduced pressure to give a paste. The paste was extracted into hexane and refiltered. The filtrate was evaporated under reduced pressure and the oil obtained was distilled to give 1-(1,1-dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane, 21.5 g, b.p. 41° C. at 0.06 mm Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:37]2[CH2:40][CH:39]([N:41]([CH3:43])[CH3:42])[CH2:38]2)[C:9]2[CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](COCC[Si](C)(C)C)[N:15]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:37]2[CH2:38][CH:39]([N:41]([CH3:42])[CH3:43])[CH2:40]2)[C:9]2[CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(c3ccc(Cl)cc3)N3CC(N(C)C)C3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cc(C(c3ccc(Cl)cc3)N3CC(N(C)C)C3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
N-{4-[4-{(4-chlorophenyl)[3-(dimethylamino)azetidin-1-yl]methyl}-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (60 mg, 0.094 mmol) was dissolved in dichloromethane (1.19 mL) and trifluoroacetic acid (0.30 mL, 3.85 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and distributed between EtOAc and saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, elution with methanol in dichloromethane, 0-20% gradient) to afford the title compound as a white solid (34.2 mg, 71.6%). LCMS: (AA) ES+ 508, 510; 1H NMR (400 MHz, d4-methanol): 8.51 (s, 1H), 8.39 (s, 1H), 8.24 (br s, 1H), 7.78 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.32 (br s, 1H), 7.26 (d, J=8.4 Hz, 2H), 5.71 (s, 1H), 3.45-3.36 (m, 2H), 3.00-2.83 (m, 3H), 2.19 (s, 3H), 2.06 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: COCCOC(=O)Cl
Product: COCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccc2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 2-methoxyethyl chloroformate to give the title compound. LC/MS (M+H)+: 637. Ret. time: 1.91 min. (Condition I); analytical HPLC Ret. time: 8.66 min (Condition H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1([CH2:6]OS(C)(=O)=O)[CH2:5][CH2:4]1.[I-].[Na+].[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[CH2:42][C:33]4([CH2:41][C:35]5([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[CH2:34]4)[O:32][C:29]3=[CH:30][N:31]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[CH2:42][C:33]4([CH2:41][C:35]5([CH2:36][CH2:37][N:38]([CH2:6][C:3]6([C:2]([F:1])([F:12])[F:13])[CH2:4][CH2:5]6)[CH2:39][CH2:40]5)[CH2:34]4)[O:32][C:29]3=[CH:30][N:31]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCN(CC4(C(F)(F)F)CC4)CC3)C2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester (45 mg) and sodium iodide (34 mg) in N,N-dimethylformamide (2 mL) is stirred at room temperature for 4 h. 5-(4-Methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 50 mg) and K2CO3 (35 mg) are added and the resulting mixture is heated to 60° C. After stirring the mixture at 60° C. for 4 h, water is added and the mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is triturated with methanol to give the title compound. LC (method 1): tR=0.82 min; Mass spectrum (ESI+): m/z=507 [M+H]+.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=O)=[N:27][CH:28]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36]C=CC=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:34][CH:35]([CH3:36])[CH2:40][CH2:32][NH:33][C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cn1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 5-(isoindoline-2-carboxamido)picolinic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (m, 2H), 8.57 (t, J=6.1 Hz, 1H), 8.17 (dd, J=8.5, 2.4 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.41-7.29 (m, 4H), 4.79 (m, 4H), 3.35 (m, 2H), 1.59 (m, 1H), 1.42 (q, J=7.1 Hz, 2H), 0.90 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 353 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][N:13]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:12]1=[O:28].[O:29]=[C:30]1[N:39]([CH:40]2[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]2)[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1>ClCCCl>[CH:25]1([CH2:24][N:13]2[CH2:14][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17][C@@H:11]([NH:10][C:46]([N:43]3[CH2:44][CH2:45][CH:40]([N:39]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:29])[CH2:41][CH2:42]3)=[O:47])[C:12]2=[O:28])[CH2:27][CH2:26]1
Reactant: N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
Diisopropylethylamine (0.16 mL, 0.90 mmol) was added to a solution of (3R,6S)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one (116 mg, 0.45 mmol) and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride (132 mg, 0.45 mmol) in 1,2-dichloroethane (10 mL) and the mixture heated to reflux. After 1 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→5% methanol/dichloromethane) gave the title compound (32 mg). MS 516 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH2:13][O:12][C:9]=3[CH:10]=2)C(=O)N(CCCCl)N=1.COC1C=[C:25]([CH2:31][CH2:32][NH:33][CH3:34])C=CC=1OC.C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[CH3:34][N:33]([CH2:32][CH2:31][CH3:25])[CH2:1][CH2:2][C:11]1[CH:6]=[CH:7][C:8]([O:15][CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=1
Reactant: Cc1nn(CCCCl)c(=O)c2cc3c(cc12)OCCO3
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: CCCN(C)CCc1ccc(OC)c(OC)c1

Procedure:
1-4-Methyl-6,7-ethylenedioxy-1(2H)-phthalazinone-2-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane was prepared analogous to Example 1 (b) by reaction of 1-[4-methyl-6,7-ethylenedioxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane with N-(3,4-dimethoxy-phenylethyl)-N-methyl-amine in chlorobenzene. Yellow oil. Rf -value (chloroform/methanol = 9/1) : 0.7.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([CH:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[CH3:28])=[CH:18][CH:17]=1)[CH3:15])[O:6]CC1C=CC=CC=1)=[O:4]>C(OCC)(=O)C>[CH3:1][NH:2][C:3]([N:5]([CH:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[CH3:28])=[CH:18][CH:17]=1)[CH3:15])[OH:6])=[O:4]
Reactant: CNC(=O)N(OCc1ccccc1)C(C)c1ccc(-n2c(C)ccc2C)cc1
Solvent: CCOC(C)=O
Product: CNC(=O)N(O)C(C)c1ccc(-n2c(C)ccc2C)cc1

Procedure:
A solution of 0.7 g of N-(N'-methylcarbamoyl)-N-benzyloxy-1-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-ethyl-amine in 50 ml of ethyl acetate is hydrogenated at room temperature and 3 atmospheres pressure for 3 hours to yield N-(N'-methylcarbamoyl)-N-hydroxy-1-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-ethylamine; m.p. 131°-133°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:24]([O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH3:26]>CCCCCCC.CCOC(C)=O>[CH2:24]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:30][CH2:29]1)[CH2:25][CH3:26]
Reactant: O=C1COc2ccccc2N1CCCCl
Reactant: CCCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCOC1CCN(CCCN2C(=O)COc3ccccc32)CC1
Yield: 76.2 %

Procedure:
4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08) (0.13 g, 0.58 mmol), K2CO3 (0.16 g, 1.15 mmol), NaI (0.17 g, 1.15 mmol) and 4-propoxypiperidine (0.089 g, 0.60 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (81(81MF08KS)) (0.147 g, 76%). 1H NMR (CDCl3) δ7.11-7.08 (m, 1H), 7.01-6.94 (m, 3H), 4.55 (s, 2H), 3.96 (t, J=7.2 Hz, 2H), 3.37 (t, J=6.8 Hz, 2H), 3.28-3.21 (m, 1H), 2.74-2.69 (m, 2H), 2.36 (t, J=7.2 Hz, 2H), 2.10-2.03 (m, 2H), 1.90-1.77 (m, 4H), 1.61-1.51 (m, 4H), 0.90 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 164.3, 145.4, 128.7, 123.8, 122.8, 117.1, 115.1, 75.1, 69.6, 67.7, 55.5, 51.5, 39.6, 31.6, 24.9, 23.4, 10.7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:2]>CO.C1COCC1.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1C#N)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1cc(N)ccc1C#N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of compound 39-1 (0.3 g) in MeOH-THF (3 mL-3 mL), was added 10% Pd/C (30 mg). The reaction mixture was stirred under hydrogen atmosphere for 3 hours at room temperature. Then the reaction mixture was filtered with Celite® pad to remove catalyst. The filtrate was concentrated in vacuo to obtain compound 39-2 (0.27 g) as pale brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[CH:31][C:32]([OH:34])=[O:33])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C:35]([O-])(O)=O.[Na+]>>[CH3:35][O:33][C:32](=[O:34])[CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C([O-])O
Reactant: CC(C)(c1cc(-c2cccc(-c3cccc(C=CC(=O)O)c3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Na+]
Product: COC(=O)CCc1cccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-acrylic acid methyl ester (1.0 eq.) from EXAMPLE 11, Step 2, in Tol (0.1M) at was added benzenesulfonyl hydrazide (3.8 eq.). The mixture was stirred at 100° C. for 12 h, cooled to rt, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 8.5:1.5) afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])=[CH:11][CH:10]=1)#[N:8].C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[OH:17][C:16]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)=[C:21]([OH:22])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)cc1
Reactant: Nc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: N#Cc1ccc(-c2c(O)nc3ncnn3c2O)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
A mixture of 14 g of 3-amino-1,2,4-triazole, 0.17 mol of the ester from example 1 and 50 ml of tributylamine (50 ml) was stirred at 180° C. for approximately 6 hours. A solution of 21 g of NaOH in 200 ml of water was added at approximately 700 and the mixture was stirred for a further 30 min. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The product precipitated from the aqueous phase after acidification with concentrated hydrochloric acid. 28 g of the title compound were obtained by filtration.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][C:12]([CH3:14])=[O:13].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH2:10][CH2:11][CH:12]([OH:13])[CH3:14]
Reactant: CC(=O)CCC1=C(C)CCCC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1=C(CCC(C)O)C(C)(C)CCC1

Procedure:
Dihydro-beta-ionone (J. Am. Chem. Soc., 108, 7314 (1986)) is reduced with sodium borohydride in ethanol in the usual fashion to provide 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanol as a colorless oil. This is coupled with 4-hydroxybenzaldehyde by the method of example 13, and the resulting aldehyde is chain-extended and condensed with glyoxylic acid by the methods of example 1. The title compound is obtained as a colorless solid, mp 99°-101° after recrystallization from hexane-chloroform
Reaction SMILES: [N+](=C)=[N-].[Si:4]([O:21][CH2:22][C@@H:23]1[C@@H:26]([CH2:27][O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25]C1=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCCCCC.CC[O:55][CH2:56][CH3:57]>>[Si:4]([O:21][CH2:22][C@@H:23]1[C@@H:26]([CH2:27][O:28][Si:29]([C:42]([CH3:43])([CH3:45])[CH3:44])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:57][C:56]1=[O:55])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](OC[C@H]1CC(=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: CCCCCC
Product: CC(C)(C)[Si](OC[C@H]1CCC(=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 17 %

Procedure:
A solution of diazomethane (ca. 2 g) in ether (200 ml) was added to (2S,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclobutanone (12.14 g, 20 mmoles) synthesized according to a method disclosed in literature Y. Ichikawa et al., J. Chem. Soc. Chem. Commun., 1919 (1989)], and the resulting mixture was stirred at room temperature for one week. After distilling off the solvent from the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (ethyl ether:n-hexane=1:10, v/v) to obtain (2S,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclopentanone (2.07 g, Yield 17%):
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH2:21][CH:22]([OH:40])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[O:24][CH2:23][CH:22]([OH:40])[CH2:21][N:12]3[CH2:13][CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11]3)=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: OC(COc1cccc(-c2ccc3c(c2)OCO3)c1)CN1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
To a solution of 5-bromobenzo[d][1,3]dioxole (100 mg, 0.49 mmol) in dioxane (4 ml) and H2O (1 mL) was added 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (300 mg, 0.73 mmol), Pd(dppf)Cl2 (36 mg, 0.049 mmol) and K2CO3 (203.2 mg, 1.47 mmol) at 12° C. The reaction mixture was stirred for 16 h at 100° C. Upon completion, the reaction mixture was concentrated to get the crude material which was purified by HPLC separation to give the title compound (146 mg, 73.7%) as a white solid. 1HNMR (CH3OD, 400 MHz) δ: 8.39 (br, 1H), 7.48-7.10 (m, 9H), 6.95-6.86 (m, 2H), 6.00 (s, 2H), 4.56-4.39 (m, 3H), 4.16-4.08 (m, 2H), 3.60-3.51 (m, 2H), 3.48-3.31 (m, 2H), 3.23-3.11 (m, 2H). LCMS (m/z): 404.2 [M+H]+