Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([N:25]([CH3:26])[CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:5])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Yield: 35.1 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.176 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N,N-dimethylhexanamide [prepared as described in Example 15(a)], 50 mg (0.18 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid, 0.28 ml (2 mmoles) of triethylamine, and 0.029 ml (0.18 mmoles) of diethyl cyanophosphate were used, to obtain 45 mg of the title compound as a white powder.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:4]2=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I:23]I.Cl>C1COCC1>[I:23][C:6]1[N:5]2[N:1]=[CH:2][CH:3]=[C:4]2[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccn2nccc12
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(I)n2nccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred suspension of pyrazolo[1,5-a]pyridine-4-carboxylic acid (29 g, 179 mmol) in anhydrous THF (1000 mL) cooled at 0° C. was added lithium hexamethyldisilazide solution (1M in THF, 200 mL, 200 mmol). After the mixture was stirred at 0° C. for 30 min, additional LHMDS solution (1M in THF, 320 mL, 320 mmol) was added at −4° C. After the mixture was stirred for 10 min, iodine (55 g, 215 mmol) was added in portions. The reaction mixture was stirred at −4° C. for 1.5 h, at rt for 1 h, and then cooled to 0° C. Aqueous HCl (5N, 40 mL) and NaS2O3 solution (10 g in 40 mL of H2O) were added. The mixture was stirred at 0° C. for 30 min, and then concentrated under reduced pressure. The residual mixture was mixed with sat. NaHCO3 solution (100 mL), ethyl ether (150 mL), and H2O (130 mL). The ether solution was separated and extracted with H2O (50 mL). The combined aqueous solutions were washed with ethyl ether (150 mL), acidified to pH=1 with saturated aqueous solution of KHSO4, heated in a steam bath, and then cooled. The solid was filtered, washed with H2O, and then dried to give compound 777C (50 g, 97%) as a yellow solid. HPLC: 100% at 2.88 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 289 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:21][CH2:22][CH3:23])[CH:12]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][S:18][C:14]=3[CH2:13]2)=[CH:6][CH:5]=1.[OH-].[Na+].O>C(O)(=O)C>[CH2:21]([N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:24])=[O:2])=[CH:9][CH:8]=1)[CH:12]1[CH2:20][CH2:19][C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH2:13]1)[CH2:22][CH3:23]
Reactant: CCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2ncsc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCN(Cc1ccc(C(=O)O)cc1)C1CCc2ncsc2C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 1.93 g (5.6 mmol) 42A, 840 mg (21 mmol) sodium hydroxide and 25 mL water is stirred for 4 hours at 80° C. The mixture is allowed to cool to room temperature and then neutralized with acetic acid and extracted three times with dichloromethane. The combined organic fractions are dried with sodium sulfate, and the solvent is evaporated in vacuum.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:15]2[C:16]3[N:8]([NH:9][CH2:10][C:11]=3[C@H:12]([CH:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:13](=[O:17])[CH:14]=2)[CH:7]=[CH:6][N:5]=1.Br>C(O)(=O)C.CO>[ClH:1].[OH:3][C:4]1[C:15]2[C:16]3[N:8]([NH:9][CH2:10][C:11]=3[C@H:12]([CH:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:13](=[O:17])[CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COC1=NC=CN2NCC3=C2C1=CC(=O)[C@H]3C1CN2CCC1CC2
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1C=C2C(O)=NC=CN3NCC(=C23)[C@@H]1C1CN2CCC1CC2
Temperature: 100 °C
Yield: 20.5 %

Procedure:
To a solution of (S)-4-methoxy-7-(quinuclidin-3-yl)-8,9-dihydro-[1,4]diazepino[6,7,1-hi]indazol-6(7H)-one (200 mg, 0.6 mmol) from Step K of Example 10 in acetic acid (5 mL) was added 48% aqueous hydrogen bromide (5 ml) and the mixture was heated to 100° C. for 3 days. After cooling to room temperature and diluting with methanol, the pH was adjusted to 8. The solvent was concentrated in vacuo and the residue was purified by prep HPLC. The product was then treated immediately with hydrochloric acid following the procedure described in Step G of Example 8 to afford (S)-4-hydroxy-7-(quinuclidin-3-yl)-8,9-dihydro-[1,4]diazepino[6,7,1-hi]indazol-6(7H)-one hydrochloride (43 mg, 21%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.98 (s, 1H), 7.76 (dd, J=2.5 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 4.71-4.60 (m, 3H), 4.12-3.98 (m, 2H), 3.83-3.68 (m, 3H), 3.41-3.34 (m, 3H), 2.54 (d, J=2.5 Hz, 1H), 2.29 (brs 1H), 2.27-2.10 (m, 2H), 2.10-1.99 (m, 1H); MS (ESI+) m/z 313 (M+H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Mg+2].[S:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1>C(N(CC)CC)C>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH:3]([NH:2][CH2:32][C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](N)c1ccc(O)cc1
Reactant: O=Cc1ccsc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NCc1ccsc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of methyl(R)-amino-(4-hydroxyphenyl)acetate hydrochloride and 100 mL of anhydrous ethyl acetate (thick suspension) are introduced at ambient temperature into a 500 mL Woulff bottle equipped with a nitrogen intake, a magnetic stirrer and a condenser. 3.1 mL of triethylamine, some magnesium sulphate and 3 g of thiophene-3-carbaldehyde are added. After 4 hours under reflux, the white solid is filtered, washed with ethyl acetate and dried under vacuum. The product is taken up in 100 mL of anhydrous dichloromethane. 14 g of sodium triacetoxy borohydride are added and the mixture is stirred at ambient temperature for 2 hours. 100 mL of methanol are added then the reaction mixture is concentrated. The product is extracted with ethyl acetate. It is washed with water then the organic phases are dried over magnesium sulphate. The mixture is concentrated, and the residue is purified over a silica column with 50/50 heptane/ethyl acetate. After concentration and crystallisation in isopropanol, a white solid is obtained (2.35 g; Yd=37%).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:11][CH2:12]1
Reactant: BrBr
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2N(C(=O)c2ccc([N+](=O)[O-])cc2)CCC1Br
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of 0.200 g of 1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one in 2.5 ml of acetic acid is warmed until solution then allowed to cool to room temperature. While stirring, a solution of 0.103 g of bromine in 0.5 ml of acetic acid is added dropwise. After rapid decolorization, the reaction mixture is stirred for 1.5 hours and poured into water. The solid is collected, washed with water and air dried to give 220 mg of the desired product as a crystalline solid, Mass Spectrum; MH+ =389,391.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@H:29]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:30][S:31]([CH2:34][C:35]([NH:38]C(=O)OCC2C=CC=CC=2)([CH3:37])[CH3:36])(=[O:33])=[O:32])=[O:28])[CH2:20][C:21]2[N:22]=[CH:23][NH:24][CH:25]=2)=[O:18])[C@@H:9]([OH:15])[C@H:10]([CH:12]2[CH2:14][CH2:13]2)[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:56]>C(O)(=O)C.[Pd]>[C:10]([OH:11])(=[O:56])[CH3:9].[C:10]([OH:11])(=[O:56])[CH3:9].[NH2:38][C:35]([CH3:37])([CH3:36])[CH2:34][S:31]([CH2:30][C@@H:29]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:27]([NH:26][C@@H:19]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:17]([NH:16][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:9]([OH:15])[C@H:10]([CH:12]1[CH2:14][CH2:13]1)[OH:11])=[O:18])=[O:28])(=[O:32])=[O:33]
Reactant: CC(C)(CS(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)NC(=O)OCc1ccccc1
Reactant: O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(N)CS(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 3 h

Procedure:
A mixture of 300 mg (0.38 mmol) of benzyl [2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulphonyl]-1,1-dimethylethyl]carbamate and 30 mg of palladium/carbon (10%) in 8 ml of acetic acid is hydrogenated at room temperature for 3 hours. Thereafter, the catalyst is filtered off, the reaction solution is evaporated and the residue obtained is lyophilized from water. There are obtained 240 mg of (S)-α-[(S)-α-[[(2-amino-2-methylpropyl)sulphonyl]methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide diacetate as a colourless, amorphous powder; MS: 646 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.O>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]([O:13][CH3:14])=[O:12])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: COC(=O)C(O)c1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OS(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
Methanesulfonyl chloride (9.3 g) was added at 0° C. to a solution of methyl 3,5-dichloromandelate (19.0 g) and triethylamine (8.2 g) in dichloromethane (150 ml). After the addition, the mixture was stirred at room temperature for 3 hours, after which water (150 ml) was carefully added. The organic phase was separated, dried and concentrated to dryness, giving methyl 2-(3,5-dichlorophenyl)-2-mesyloxy-acetate (23.6 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O=[Pt]=O.CCO>[C:8]1([CH2:7][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCCO
Agent: O=[Pt]=O
Solvent: CCO
Product: OCCCCNCc1ccccc1

Procedure:
Combine 4-amino-butan-1-o1 (8.9 gm - 0.1 mol), benzaldehyde (10.6 gm - 0.1 mol), EtOH (100 ml) and PtO2 (0.3 gm), and hydrogenate the mixture at 45 lbs./sq.in. until H2 is no longer taken up. Filter, evaporate the solvent (in vacuo) to yield 17.7 gm of the desired compound. Rf is 0.70 (eluted from silica gel with 10% conc. NH3 /CH3OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.[CH3:32][NH:33][CH3:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:33]([CH3:34])[CH3:32])=[O:18])=[N:14][CH:15]=1
Reactant: CNC
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)C)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.8 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridine-2-carboxylic acid (352 mg, 0.80 mmol) in methylene chloride (10 ml), dimethylamine hydrochloride (73 mg, 0.88 mmol), 1-hydroxybenzotriazole (119 mg, 0.88 mmol) 4-methylmorpholine (0.194 ml, 1.76 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (169 mg, 0.88 mmol) were added at room temperature. After stirring for 13 hours at room temperature, the reaction mixture was washed with 0.5 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain the title compound (370 mg, 0.79 mmol, 99%) as a colorless oily substance.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:6][N:5]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])([OH:3])=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[Cl:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([S:10]([N:8]1[CH2:7][CH2:6][N:5]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)=[O:25])[CH:4]([C:1]([NH:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:3])[CH2:9]1)(=[O:12])=[O:11])[CH:22]=[CH:21]2
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1

Procedure:
In a similar manner to Example 4 except for the use of 4-[4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide and 4-(2-aminoethyl)morpholine as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)(O)=[O:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:1](=[O:2])[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Reactant: Nc1ccccc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)Nc2ccccc2)cc1

Procedure:
Analogously to Example 3a, 3.06 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 34b) and 0.63 ml of aniline are reacted. The title compound is obtained as a colourless oil. Rf=0.50 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])CCC.[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C>C(O)C>[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH:36][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Yield: 98.3 %

Procedure:
A mixture of 1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (45 mg, 0.12 mmol) (prepared according to U.S. Pat. No. 7,629,357) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (50 mg, 0.29 mmol) in ethanol was microwaved at 140° C. for 1 h. Reaction mixture was quenched with acetic acid (3 equivalents) and concentrated. Residue was purified by silica gel chromatography, eluting with 5-50% EtOAc/hexanes to provide the title compound 55 mg (0.118 mmol) in 98% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 13.92 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 7.42 (m, 2H), 4.56 (br s, 1H), 3.55 (d, J=6.2 Hz, 2H), 2.04 (br m, 2H), 1.83 (br m, 2H), 1.56-1.24 (m, 21H).
Reaction SMILES: C([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH-:38])=O)CCCCCCC/C=C\CCCCCCCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.O>C1COCC1.C(Cl)Cl>[CH2:19]([NH:38][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]/[CH:28]=[CH:27]\[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCCCC/C=C\CCCCCCCC([NH-])=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCCNCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C

Procedure:
A solution of N-oleyloleoylamide (prepared above) in THF (100 mL) was warmed to 40° C. Lithium aluminum hydride was slowly added until violent evolution of gas ceased. The reaction mixture was heated to reflux for one hour and then cooled to room temperature. Methanol (100 mL) was slowly added, followed by water (200 mL). Methylene chloride was added and the resultant suspension was stirred for fifteen minutes. The slurry was filtered and the precipitate was washed with ethanolmethylene chloride (50:50, 50 mL, 2×). The combined filtrates were extracted with methylene chloride. The organic fraction was dried over magnesium sulphate, filtered and the solvent was removed under vacuum. The residue was passed down a silica gel column (150 g) using 5% methanol in methylene chloride as the eluent, to provide dioleylamine as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([C:15](O)=[O:16])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[Cl-].[NH4+]>C(#N)C.CN(C1C=CN=CC=1)C>[Cl:25][C:20]1[CH:19]=[C:18]([C@@H:12]2[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C@H:13]2[C:15](=[O:16])[NH:30][S:27]([CH3:26])(=[O:29])=[O:28])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)O)C1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of (6R,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-6-carboxylic acid (590 mg) in acetonitrile (15.1 mL) were added N,N-dimethyl-4-aminopyridine (203 mg), methanesulfonamide (158 mg) and 2-methyl-6-nitrobenzoic anhydride (625 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (323 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:17](O)=[O:18]>>[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:17]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1)=[O:18]
Reactant: Cc1ccc2ccc(N)cc2n1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccncc1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccncc4)c(C)c3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (30 mg, 0.19 mmol) and 3-methyl-4-(4-pyridyl)benzoic acid (D57) (49 mg, 0.23 mmol) as an orange gum, (59 mg, 88%). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.70 (dd, 2H), 8.10 (s, 2H), 8.03 (m, 2H), 7.87 (s, 1H), 7.80 (d, 2H), 7.35 (d, 1H), 7.27 (m, 3H), 2.74 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=[C:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(Cc2ccc(-c3ccccc3)[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of 2-benzyl-5-phenyl-1H-pyrrole (467 mg, 2.0 mmo) in DMF (5 ml) was added NaH (60% in mineral oil, 240 mg, 6.0 mmol) at room temperature in one portion. After stirring for 30 min at room temperature, the reaction mixture was heated to 60° C. and methyl bromoacetate (0.57 ml, 6.0 mmol) was added. After 1 h stirring at 60° C., the reaction was cooled and quenched with aqueous 1N HCl (30 ml). The aqueous was extracted with EtOAc (3×30 ml). The combined organic extracts were washed with aqueous 1N HCl (30 ml), H2O (30 ml), brine (30 ml), dried (MgSO4) and concentrated. The crude material was purified by chromatography (EtOAc/hexane: 3/97) to afford the titled compound (240 mg, 39%) as an oil: MS (+) ES, 306 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2ccc(F)c(Cl)c2F)n1
Product: Cc1cc(Cl)nc(/C=C/c2ccc(F)c(Cl)c2)n1
Yield: 83.3 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(3-chloro-4-fluorofluoro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (1.85 g, 7 mmol) in POCl3 (12.83 ml, 0.14 mol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-6-methyl-pyrimidine (1.65 g, 83%) as a yellow solid. EI mass spectrum, m/e: 282 (M+1 calculated for C13H9Cl2FN2: 282).