Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:14]1
Reactant: NC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCNC3)oc12
Yield: 241.6 %

Procedure:
A mixture of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (200 mg, 0.27 mmol), 10% Pd/C (40 mg) in methanol (30 ml) was stirred at room temperature over 1 atm hydrogen for 2 hr. Then the mixture was filtered and evaporated, 160 mg of 2-(piperidin-3-yl)benzo[d]oxazole-7-carboxamide as a solid was obtained. Yield 24%. LC-MS (ESI) m/z: 246 (M+1)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.C(O)(=O)[C:11](O)=[O:12].[C:16]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17]>>[C:16]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:17])[CH3:18].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=[O:12]
Reactant: O=C(O)C(=O)O
Agent: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Solvent: O
Solvent: Oc1ccccc1
Product: C=O
Temperature: 160 °C

Procedure:
Phenol (141 g; 1.5 moles) and 2.5 g of oxalic acid dihydrate were added to the resol layer, and the mixture was heated to perform co-condensation reaction of the p-tert-octylphenol resol with phenol. While distilling off the resulting water and volatile matter under atmospheric pressure and then under reduced pressure, the reaction mixture was heated to 160° C. to give 358 g of a pale yellow p-tert-octylphenol/phenol/formaldehyde co-condensate having a softening point of 85° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[OH:25]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[O:25][C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[CH:2]=[CH:3][C:4]=1[C:5]#[N:6]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1cc(CC(=O)O)ccc1Cl

Procedure:
The title compound was prepared by the method of example 2 step (iii) using 3-fluoro-4-(trifluoromethyl)benzonitrile and the product of example 1 step (iii).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].[CH:12](I)([CH3:14])[CH3:13].Cl>C(O)C>[NH2:3][C@@H:4]([C:5]([S:8][CH:12]([CH3:14])[CH3:13])([CH3:7])[CH3:6])[C:9]([OH:11])=[O:10]
Reactant: CC(C)I
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)SC(C)(C)[C@H](N)C(=O)O
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
NaH (1.3 g) was added in portions to 70 mL ethanol while cooling. Subsequently D-penicillamine (4.0 g) was added. The mixture kept stirring for 5 minutes at 5° C., after which isopropyl iodide (2.8 mL) was added, The mixture was allowed to stir 16 h at ambient temperature. 2 N HCl was added followed by evaporation of the volatiles to give 11.9 g crude 2-(R)-amino-3-isopropylsulfanyl-3-methyl-butyric acid, which was used in the next step without further purification.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)([CH3:14])[CH3:13].[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].[NH4+].[Cl-]>C1COCC1>[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:24])[CH:22]=[CH2:23])([CH3:14])[CH3:13]
Reactant: C=CC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Production in a way similar to: D. A. Evans, K. T. Chapman, J. Bisha J. Am. Chem. Soc. 1988, 110, 1238; A Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185. 6.88 ml of a 1.6M solution of n-BuLi in hexane (11.0 mmol) is slowly added to a solution of 1.299 g (10.0 mmol) of (S)-4-isopropyl-oxazolidin-2-one in 15 ml of absolute THF at -78° C. The solution is stirred for 30 minutes at -78° C.; 1.22 ml (15.0 mmol) of acrylic acid chloride is added drop by drop; it is allowed to reach room temperature and hydrolyzed with 50 ml of saturated NH4Cl solution. It is extracted three times with 50 ml of Et2O each. After drying on MgSO4, the solvent is removed. By flash-chromatographic purification with pentane/Et2O (10:1), 1.63 g (8.9 mmol, 89%) of 20 is obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:30][O:31][C:32](=[O:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39](=O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH3:30][O:31][C:32](=[O:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39](=[CH:2][O:3][CH3:4])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:34]=1
Reactant: CCCCCCC(=O)c1ccc(C(=O)OC)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCC(=COC)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (10.34 g, 30.24 mmol) is suspended in anhydrous toluene (75 mL) and potassium tert-butoxide (3.39 g, 30.24 mmol) is carefully added. The solution is allowed to stir at room temperature for 4 h. 4-Heptanoyl-benzoic acid methyl ester (5.0 g, 20.16 mmol) is then dissolved in anhydrous toluene (25 mL) and added to the reaction mixture by cannula. The reaction is allowed to stir at room temperature overnight and is monitored by TLC. Upon complete consumption of starting material, the reaction is carefully quenched with saturated ammonium chloride solution, extracted with diethyl ether, washed, dried, and concentrated. The title compound is purified by column chromatography using hexanes/ethyl acetate and used directly in the next step.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CN3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CN3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4,5-dihydro-1,2,4-triazin-6(1H)-one-3-yl)pyridinium bromide (300 mg, 0.74 mmol) was dissolved in methanol (8 ml), gradually added with sodium borohydride (280 mg, 7.4 mmol) under ice cooling and stirred at room temperature overnight. The solvent was removedunder reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (165 mg) ascolorless plates.
Reaction SMILES: [CH3:1][Mg+].[Br-].[C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]=[O:21])=[CH:15][CH:16]=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH4+].[Cl-]>C1COCC1>[C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]([OH:21])[CH3:1])=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into the THF (50 ml) solution of MeMgBr (3M in Et2O, 5.6 mL, 1.5 eq.) was added dropwise the THF (40 ml) solution of 2-phenylquinoline-7-carbaldehyde (2625 mg, 11.25 mmol) under N2 at rt over 20 min. After stirring at rt for 3 h, the reaction mixture was treated with saturated aqueous NH4Cl solution (100 ml), and the organic phase was separated. The aqueous phase was extracted with EtOAc (2×100 ml). The combined organic phases were then washed with H2O (2×100 ml) and brine (100 ml), dried over MgSO4, filtered and concentrated to give the title compound as brown oil. The crude material was used for the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ=1.60-1.62 (d, 3H, J=6.4 Hz), 2.08 (brs, 1H), 5.11-5.14 (m, 1H), 7.44-7.60 (m, 4H), 7.81-7.83 (d, 1H, J=8.4 Hz), 7.85-7.87 (d, 1H, J=8.4 Hz), 8.13-8.17 (m, 3H), 8.19-8.21 (d, 1H, J=8.4 Hz). MS (ES+): 250.3 [MH+]. HPLC: tR=2.9 min (MicromassZQ, polar—5 min).
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.NN.[CH3:14][N:15]=[C:16]=[S:17].[CH3:18][C:19]1[N:20]=[C:21]([S:24][CH2:25][CH2:26][CH2:27][NH:28]C(N)=S)[O:22][CH:23]=1>>[CH3:14][NH:15][C:16]([NH:28][CH2:27][CH2:26][CH2:25][S:24][C:21]1[O:22][CH:23]=[C:19]([CH3:18])[N:20]=1)=[S:17]
Reactant: Cc1coc(SCCCNC(N)=S)n1
Reactant: CN=C=S
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Product: CNC(=S)NCCCSc1nc(C)co1

Procedure:
Treatment of the phthalimide compound (3.0 g.) with hydrazine (1.53 g.) followed by reaction of the product directly with methyl isothiocyanate (0.73 g.) using the conditions described in Example 132 afforded N-methyl)-N-[3-(4-methyl-2-oxazolyl)thiopropyl]thiourea (1.0 g.). m.p. 73°-74° (from ethanol-ether-n-hexane).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:43](=[O:44])[NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.396 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine are reacted with 45 mg (0.377 mmol) of phenyl isocyanate in analogy to Example 16a. The title compound ##STR80## is obtained as solid residue (129 mg, 52%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.42, FD-MS: M+ 622, 624.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[B](F)F.[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:29])=[C:21](F)[C:22]=3[O:24][CH:25]([F:27])[F:26])[C:17](=[O:30])[C:16]([C:31]([OH:33])=[O:32])=[CH:15]2)[CH2:13][CH2:12]1.O>CS(C)=O>[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:29])=[C:21]([N:6]4[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]4)[C:22]=3[O:24][CH:25]([F:26])[F:27])[C:17](=[O:30])[C:16]([C:31]([OH:33])=[O:32])=[CH:15]2)[CH2:12][CH2:13]1
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: F[B]F
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC(F)F)CCN1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
1.63 g (0.016 moles) of 2-methylpiperazine was added to a solution of 2.58 g (0.0068 mole) of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate (prepared as described in Preparation 8) in 20 ml of dimethyl sulfoxide, and the mixture was allowed to stand at room temperature overnight, The reaction mixture was then poured into 100 ml of water, and the crystals which precipitated were collected by filtration and washed with water. The crystals were then dissolved in 500 ml of 80% v/v aqueous methanol containing 15 ml of triethylamine, and the solution was heated under reflux for 3 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was washed with ethanol, to give 2.30 g of a pale yellow powder. The whole of this powder was dissolved in 50 ml of water, insoluble materials were removed by filtration, and the filtrate was adjusted to a pH value of 7.5 by the addition of a 1N aqueous solution of sodium hydroxide. The crystals which precipitated were collected by filtration and washed with water and with ethanol, in that order, to give 1.74 g of the title compound as fine pale yellow needles, melting at 223°-225° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([O:72][C:73]([F:76])([F:75])[F:74])[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([O:72][C:73]([F:74])([F:75])[F:76])=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(OC(F)(F)F)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC(F)(F)F)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 60 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-trifluoromethoxy-benzaldehyde were reacted to produce the title compound (60%). 1H NMR (d-chloroform): 13.94 (br s, 1H), 8.31 (d, J=9 Hz, 1H), 8.20 (d, J=9 Hz, 1H), 7.83 (s, 1H), 6.97 (d, J=9 Hz, 1H), 6.82 (s, 1H), 6.44 (m, 2H), 6.24 (s, 1H), 5.82 (s, 1H), 5.35 (d, J=9 Hz, 1H), 4.11 (s, 3H), 3.17 (s, 1H), 2.97 (s, 1H), 2.74 (d, J=8 Hz, 1H), 2.31 (d, J=9 Hz, 1H), 1.65 (d, J=9 Hz, 1H). MS: 495.00 (M+H). HPLC retention time: 3.12 minutes (G Method).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[C:17]([O:16][C:14]([N:8]1[CH2:13][CH2:12][N:11]([C:2]2[S:3][C:4]([Br:7])=[CH:5][N:6]=2)[CH2:10][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 160 °C
Yield: 68 %

Procedure:
A mixture of 24.7 mmol 2,5-dibromothiazole, 49.4 mmol tert-butyl 1-piperazinecarboxylate and 74.1 mmol triethylamine in 24 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 30 min under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 68%). MS (m/e): 350.2 ({81Br}M+H+, 100%), 348.2 ({79Br}M+H+, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12](O)=[O:13])[CH:7]=1.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:13])[CH:7]=1
Reactant: NCCCCCCO
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)O)cc1Cl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)NCCCCCCO)cc1Cl

Procedure:
The reaction and work up was conducted as described in the preparation of compound 205. Starting compounds were N-(5-bromo-2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (600 mg, 1.16 mmol) (prepared by a similar method as described in WO 01/05746) and 6-aminohexanol (151 mg, 1.28 mmol). The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]([C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=O)[CH:7]=1.Cl.[NH2:27][OH:28]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6](/[C:8](/[C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=[N:27]/[OH:28])[CH:7]=1
Reactant: NO
Reactant: COc1ccc(F)cc1C(=O)c1nccc(-c2cnccc2C)c1F
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1/C(=N/O)c1nccc(-c2cnccc2C)c1F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of (5-fluoro-2-methoxyphenyl)(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)methanone (0.024 g, 0.071 mmol) and hydroxylamine hydrochloride (0.033 g, 0.480 mmol) in pyridine (Volume: 0.353 ml) was refluxed for 3 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-95% EtOAc in hexanes over 15 min, tr=0.5, 1.5, 2.5 min) gave the title compound (22 mg, 0.061 mmol, 87% yield) as a yellow residue. ESI MS (M+H)+=356.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:33])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10].[OH-].[K+]>O.CO>[Cl:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)CNc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NCC(=O)O)cc12
Yield: 53.3 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide (Example 52) (100 mg, 0.204 mmol) was hydrolysed using potassium hydroxide (5 eq.) in 3 ml water and 3 ml methanol for 12 h at room temperature. The solid precitated was filted and washed with ethanol to obtain the product as pale yellow solid (50 mg). mp: >260° C.
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:40](Cl)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>ClCCl>[CH3:42][C:41]([CH3:44])([CH3:43])[C:40]([N:8]1[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[NH:4][C:3]1=[O:2])=[O:45]
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(=O)N(C(=O)C(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.96 g., 3.0 mmole), dry triethylamine (1.25 ml., 9.0 mmole), and dimethylaminopyridine (36 mg., 0.3 mmole) in dichloromethane (12 ml.) under argon is treated with pivaloyl chloride (0.44 ml., 3.6 mmole). After stirring for 45 minutes at room temperature, the reaction mixture is evaporated. The residue is taken up in tetrahydrofuran/methanol (10 ml. each) and treated with 2N hydrochloric acid (6.0 ml., pH 1). After stirring at room temperature for 3.0 hours, the reaction is quenched with saturated sodium bicarbonate, partially evaporated and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride and evaporated. Flash chromatography and crystallization from dichloromethane/isopropyl ether gives the title compound as white crystals (420 mg. , m. p. 155°-156°. TLC(silica gel; ethyl acetate:hexane, 1:1)Rf =0.67.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH2:19]([O:21][SiH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:20]>>[NH2:4][CH2:1][CH2:2][CH2:3][Si:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:21][CH2:19][CH3:20]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCN
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCO[Si](CCCN)(OCC)OCC
Yield: 65 %

Procedure:
571 parts of allylamine, 0.38 part of [Rh(NBD)2 ](+). BF4(-) (note: NBD: Norbornadiene), 1.0 part of phenothiazine and 1640 parts of triethoxysilane were charged into a sealed tube and allowed to react in an oil bath for 2 hours at 130° C. Following cooling, the product was analyzed with gas chromatography. Aminopropyltriethoxysilane was produced at a yield of 65% and moreover, the ratio of γ:β isomer was 24:1.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27]([OH:29])=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](OC(=N)C(Cl)(Cl)Cl)([CH3:33])([CH3:32])[CH3:31].B(F)(F)F.CCOCC>C1COCC1>[C:30]([O:28][C:27]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[OH:26])=[O:15])[CH2:12][N:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Temperature: 0 °C
Yield: 34 %

Procedure:
A mixture of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid (50 mg, 0.13 mmol) and 2,2,2-trichloro-acetimidic acid tert-butyl ester (70 mg, 0.33 mmol) in THF (1 mL) was stirred at 0° C. for several minutes. Then BF3.OEt2 (20 mg, 0.13 mmol) was added dropwise at 0° C. and the reaction mixture was warmed to room temp. and stirred for 2 h. The reaction mixture was then quenched with brine solution, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (using 5% EtOAc in hexane as eluent) to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid tert-butyl ester (20 mg, 35.0% yield) as a bluish sticky liquid. MS calcd. for C27H37N2O4 [(M+H)+] 453.0, obsd. 453.2.