Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:24]=[C:25]1[NH:30][CH2:29][CH2:28][CH2:27][N:26]1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:34]2[CH2:35][CH2:36][CH:31]([N:26]3[CH2:27][CH2:28][CH2:29][NH:30][C:25]3=[O:24])[CH2:32][CH2:33]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CN1C(=O)c2ccccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 160.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.333 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.183 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in Example 8 to afford the title compound (0.424 g); mp 160°-185° C.; MS: m/z=514(M+1); NMR(CD3SOCD3): 1.65 (d,2, J=13), 1.78 (s,1), 2.18 (m,2), 3.06 (s,3) 4.39 (m,1), 4.87 (d,1, J=3.5), 6.77 (d,1, J=8.4), 6.96 (s,1), 7.33 (d,1, J=8.3), 7.50 (m,2), 7.67 (m,1), 7.94 (d,1, J=7.6). Analysis for C27H32 Cl2N4O2.2.0 HCl.0.5 H2O: Calculated: C, 54.28; H, 5.90, N, 9.37; Found: C, 54.36; H, 5.86; N, 9.10.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1.[CH3:27][NH2:28].Cl.CCOCC>CS(C)=O.O>[ClH:1].[CH3:27][NH:28][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: CN
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CNCCOc1ccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 6-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.075 g, 0.19 mmoles) and methylamine (0.28 mL, 0.56 mmoles) in DMSO (1 mL) was stirred under nitrogen at 100° C. for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCl in ether (0.2 mL, 0.2 mmoles) was added, then dried, to afford the title compound as the HCl salt (0.07 g, 0.19 mmoles), MS: (ES+) 381 [M+H]+
Reaction SMILES: C(NCC)C.O.[CH2:7]([O:9][C:10](=[O:30])[CH:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[C:12](O)=O)[CH3:8].C=O>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:30])[C:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)=[CH2:12])[CH3:8]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)O
Agent: C=O
Solvent: O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Diethylamine (0.29 g, 3.00 mmol), water (2 mL) and methylene chloride (2 mL) was added to a mixture of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.00 g, 2.96 mmol) and 37% aq. solution of formaldehyde (0.25 g, 3.05 mmol) at 0° C. The mixture was stirred for 16 h at room temperature and then poured onto ice-water and extracted with methylene chloride. The organic layer was washed with 5% NaHCO3 and dried. Filtration and concentration under reduced pressure gave 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.75 g, 83%).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[O:22][C@@H:21]([C:23]([OH:25])=[O:24])[C@H:20]([NH:26][C:27](=[O:29])[CH3:28])[C@@H:19]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:18]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:49]1[C:54]([F:55])=[C:53]([F:56])[C:52]([F:57])=[C:51]([F:58])[C:50]=1[F:59])=O>CN(C)C=O.C(OCC)(=O)C>[F:55][C:54]1[C:53]([F:56])=[C:52]([F:57])[C:51]([F:58])=[C:50]([F:59])[C:49]=1[O:24][C:23]([C@H:21]1[C@H:20]([NH:26][C:27](=[O:29])[CH3:28])[C@@H:19]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:18]=[C:17]([C:15]([O:14][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[O:22]1)=[O:25]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(=O)N[C@@H]1[C@@H](NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H]1[C@@H](NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F

Procedure:
(2R,3R,4S)-3-Acetylamino-4-(tert-butoxycarbonylamino)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid 6-benzhydryl ester (3.36 g) was dissolved in dry dimethylformamide (10 ml) and pyridine (0.632 g) under nitrogen and stirred at 23° C. To this was added pentafluorophenyl trifluoroacetate (2.02 g). After 3 hours the reaction mixture was diluted with ethyl acetate (250 ml) and washed with dilute hydrochloric acid (3×50 ml), dilute sodium bicarbonate solution (3×50 ml) and brine (50 ml). The organic phase was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo to give the title compound as an off-white foam. (4.353 g); 1H NMR (250 MHz, DMSO) 8.22 (1H, d, J=8Hz), 7.50-7.27 (10H, m), 7.06 (1H, m), 6.94 (1H, s), 6.18 (1H, d, J=3.8Hz), 5.25 (1H, d, J=6.8Hz), 4.42 (1H, m), 4.29 (1H, m), 1.82 (3H, s), 1.38 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:13]=1[NH2:14].C(N(C(C)C)CC)(C)C>CC(O)C>[C:19]([C:16]1[CH:17]=[CH:18][C:12]([CH3:11])=[C:13]([NH:14][C:6]2[C:5]([O:9][CH3:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(C(C)(C)C)cc1N
Reactant: COc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Cl)nc1Nc1cc(C(C)(C)C)ccc1C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A solution of 2,4-dichloro-5-methoxypyrimidine (200 mg, 1.12 mmol), 2-methyl-5-t-butylaniline (192 mg, 1.17 mmol) and diisopropylethylamine (1.5 mL) in 2-propanol (1.5 mL) was heated at 120° C. for 17 h in an oil bath. The mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage system, EtOAc/Hexane, 0%-100%) to afford the product as a solid (166 mg, 48.6%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1)[OH:4].[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.O1CCOCC1>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:2]([F:1])([F:19])[F:20])[N:23]=1
Reactant: N#Cc1ccc(-c2ccccc2C(O)C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccccc3-c3ccc(C#N)nc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 110 °C
Yield: 84 %

Procedure:
A mixture of 5-[2-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-pyridine-2-carbonitrile (46 mg, 0.165 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (59 mg, 0.15 mmol), cesium carbonate(195 mg, 0.6 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature, then was poured into 5 ml of water. 1N HCl was added to adjust pH to 4.5, the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated to give 80 mg of crude (S)-3-[4-(2-amino-6-{1-[2-(6-cyanopyridin-3-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid, yield 84%.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CO)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a well stirred solution of 2-hydroxyacetophenone (1.0 g, 7.34 mmol) in dichloromethane (15 mL) is added triethylamine (1.23 mL, 8.81 mmol), 4-dimethylaminopyridine (45 mg, 0.367 mmol) and tert-butyldimethylsilyl chloride (1.16 g, 7.71 mmol) dissolved in dichloromethane (2 mL). The reaction mixture is stirred at room temperature for 1 h, then diluted with dichloromethane (50 mL), washed with 10% citric acid, saturate sodium carbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (20% ethyl acetate in hexanes) to yield the title compound as a yellow oil (1.3 g, 5.19 mmol).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[C:7](/[N:9]=[C:10](\[N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)/[N:11]1[CH2:16][CH2:15][C@H:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[CH3:33])[CH2:21][CH2:20]2)=[O:18])[C@@H:13]([C:34](OC)=[O:35])[CH2:12]1)#[N:8].NO>CO>[C:7](/[N:9]=[C:10](\[N:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)/[N:11]1[CH2:16][CH2:15][C@H:14]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[CH3:33])[CH2:23][CH2:24]2)=[O:18])[C@@H:13]([C:34]([NH:2][OH:3])=[O:35])[CH2:12]1)#[N:8]
Reactant: NO
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C#N)ccc1N1CCN(C(=O)[C@H]2CCN(/C(=N/C#N)N3CCCCC3)C[C@@H]2C(=O)NO)CC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (1.56573 g, 0.0223062 mol) in anhydrous methanol (6.0 mL) at rt was added 4.37 M of sodium methoxide in methanol (7.64 mL). The reaction mixture was heated at 55° C. for 5 min, cooled to rt, then to 0° C. Filtration afforded a clear solution assumed to be ca. 1.50 M in methanol. To a stirred solution of methyl(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (53.30 mg, 0.0001054 mol) in anhydrous methanol (1.110 mL, 0.02740 mol) at rt was added the above 1.50 M of hydroxylamine in methanol (1.40 mL). The reaction mixture was stirred at rt for 2 h. LCMS showed the reaction was done. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC with 5-95% MeCN/H2O to give the product. MS (ESI): (M+H)+=507.
Reaction SMILES: Cl.[CH:2]([O:5][NH2:6])([CH3:4])[CH3:3].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:18][C:19](=O)[CH2:20][CH3:21]>C(O)C>[CH2:20]([C:19]1[N:6]([O:5][CH:2]([CH3:4])[CH3:3])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:21]
Reactant: CCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: CC(C)ON
Agent: Cl
Solvent: CCO
Product: CCc1nc2cnc3ccccc3c2n1OC(C)C
Temperature: 25 °C
Yield: 94.9 %

Procedure:
O-isopropylhydroxylamine hydrochloride (2.5 g, 1.7 eq) was added to a solution of N-(4-chloroquinolin-3-yl)propionamide (3.1 g, 1.0 eq) in ethanol (150 mL). The reaction mixture was heated at reflux for 3 hours, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 3.2 g of 2-ethyl-1-isopropoxy-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:33][O:34][C:35](=[O:40])[C@H:36]([CH2:38][OH:39])[NH2:37]>ClCCl.C(Cl)(Cl)Cl>[CH3:33][O:34][C:35](=[O:40])[C@H:36]([CH2:38][OH:39])[NH:37][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CO)NC(=O)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To an ice cooled solution of 3,5-difluorophenylacetic acid (2.16 g) in anhydrous dichloromethane (100 mL) under nitrogen was added HOBt-hydrate (4.23 g), EDAC-HCl (3.6 g), and NMM (2.2 mL). The reaction mixture was stirred at 0° C. under nitrogen for 15 min and L-serine methyl ester-HCl (1.96 g) was added followed by NMM (1.38 mL). The reaction was stirred at 0° C. for 1H and RT for 2H. The reaction mixture was concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, dilute aqueous sodium bicarbonate, brine, dried, filtered and the solvent removed in vacuo to yield a white solid. Trituration with CHCl3 afforded pure title compound (1.8 g). The impure filtrate was subjected to flash chromatography (20% acetone/CHCl3) to afford additional title compound (800 mg, total yield 76%). 1H NMR (300 MHz, d6-DMSO) δ3.57 (d, 2H), 3.62 (s, 3H), 3.7 (m, 1H), 4.35, (m, 1H), 5.1 (bs, 1H), 7.00 (d, 2H), 7.09 (t, 1H), 8.53, (d, 1H). MS APCI m/z=274 (M+1). LC/MS: 1.34 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 91, 100.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded the title compound as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([Br:16])[C:18]=1[CH3:24])=[O:10]
Reactant: Cc1c(N)cccc1Br
Reactant: Cc1cccc(C(=O)O)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
A mixture of thionyl chloride (3.15 g, 26.5 mmol) and 2-amino-3-methylbenzoic acid (2.00 g, 13.23 mmol) in THF (50 mL) was heated at reflux for 2 h. The cooled mixture was concentrated and the residue was combined with 3-bromo-2-methylaniline (4.92 g, 26.5 mmol) in THF (50 mL) and heated at reflux for 5 h. The mixture was cooled to room temperature, treated with 10% aqueous K2CO3 and stirred at room temperature for 30 min. The resulting mixture was extracted 3 times with DCM, and the combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-20%), to give 2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide as a yellow solid (1.71 g, 40% yield). Mass spectrum m/z 319, 321 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.70 (d, J=7.9 Hz, 1H), 7.64 (br. s., 1H), 7.50-7.40 (m, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.70 (t, J=7.6 Hz, 1H), 5.67 (br. s., 2H), 2.44 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:18][N+:19]([O-:21])=[O:20])=[NH:22])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC(=N)N[N+](=O)[O-])o1

Procedure:
A solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and S-methyl-N-nitroisothiourea (1.5 g) in ethanol (10 ml) was heated to 40° for 5 mins. The resulting precipitate was filtered and recrystallised from ethyl acetate and petroleum ether b.p. 80°-100° to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-nitroguanidine m.p. 103°-104°.
Reaction SMILES: C(N)(C)(C)C.[CH3:6][O:7][C:8](=[O:20])[C:9](=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12].[H][H]>CO>[CH3:6][O:7][C:8](=[O:20])[CH:9]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(CC(=O)O)=C1CCCCC1
Reactant: [H][H]
Solvent: CO
Solvent: CC(C)(C)N
Product: COC(=O)C(CC(=O)O)C1CCCCC1
Temperature: 0 °C
Yield: 109.4 %

Procedure:
The tert-butylamine salt of 2-cyclohexylidenesuccinic acid 1-methyl ester (0.91 g, 3.2 mmol) was placed in a 60 mL high pressure hydrogenation vessel and the vessel was purged with hydrogen (by pressurizing and venting three times with 10 bar of hydrogen). Methanol (9 mL, previously degassed by bubbling nitrogen for one hour at room temperature under stirring) was added through the solvent port and the vessel was then cooled to 0° C. A solution of [Rh(COD)(RR)Me-BPE]OTf (0.004 g, 0.0065 mmol, substrate/catalyst: 500/1) in methanol (1 mL) was added and the reactor was charged with 10 bar of hydrogen. The reaction was stirred at 0° C. for 20 hours, then the solvent was evaporated under reduced pressure and the residue was partitioned between HCl 2N (20 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over MgSO4, evaporated to give 0.75 g of 2-cyclohexylsuccinic acid monomethyl ester as a pale yellow oil (yield 82%). The enantiomeric excess of 2-(R)-cyclohexylsuccinic acid 1-methyl ester was 96% by GC.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nc[nH]n1
Product: Nc1ccc(-n2cncn2)cc1

Procedure:
The title compound is obtained as described in Example 18a/b using 1-fluoro-4-nitro-benzene (Fluka, Buchs, Switzerland) and 1,2,4-triazole (Fluka, Buchs, Switzerland). Title compound: ES-MS: 161.2 (M+H)+; analytical HPLC: tret=3.29 minutes (Grad 2).
Reaction SMILES: [CH:1]1([CH:4]([OH:45])[CH2:5][O:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:37][C:36](=[O:38])[O:35][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:39][CH2:40][CH3:41])[N:15]4[N:42]=[CH:43][CH:44]=[C:14]34)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4](=[O:45])[CH2:5][O:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:37][C:36](=[O:38])[O:35][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:39][CH2:40][CH3:41])[N:15]4[N:42]=[CH:43][CH:44]=[C:14]34)[CH2:11][CH2:12]2)[CH2:2][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C3CC3)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C3CC3)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.25 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.35 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:16]([C:38]3[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:44][C:41]1([CH3:45])[CH2:42][CH2:43][C:38]([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])=[CH:39][CH2:40]1
Reactant: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 88.5 %

Procedure:
A solution of 124 mg (0.196 mmol) 4-[4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 200 μL MeOH and 3 mL TFA at RT for 3.5 h. Solvents were evaporated in vacuo. The residue was taken up in CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 70.0 mg (89%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C24H29N5O, 404.2 (M+H), found 404.3.