Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>CC1CCCO1.C1COCC1>[OH:26][CH:25]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[CH2:29][C:28]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(C)=O
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CCOC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Under argon atmosphere, 8.3 mL (4.43 mmol, 1.5 equivalent) of the solution of ethyl bromozincacetate in 2-methyltetrahydrofuran obtained in Example 67 was added dropwise to a solution of 1 g (2.96 mmol) of 1-trityl-1H-imidazol-4-carbaldehyde in 10 mL of THF at 5˜8° C. The mixture was stirred at 3˜6° C. for 2 hours and 20 minutes. The mixture was stirred at 20˜25° C. for 1 hour and 15 minutes. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 15 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, recrystallization with 5 mL of IPE afforded 1.04 g of the desired product (yield 83%).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](O)=[O:18].N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:14]([Cl:13])[CH:15]=3)[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)c(Cl)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 3,4-dichlorobenzoic acid (Aldrich) according to methods A and C; yield 49 mg, 0.15 mmol (69%): 1H NMR (300 MHz, methanol-d4) δ 1.96 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=14 Hz, 2H), 2.46 (s, 2H), 3.57 (s, 2H), 3.67 (s, 4H), 4.39 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.77 (dd, J=8, 2 Hz, 1H), 8.02 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 325 (M+H)+; Anal. C16H18Cl2N2O.HCl: C, H, N.
Reaction SMILES: C(C1ON=C(NC(NC2C=CC=C(OC3C4C(=CC(O)=C(OC)C=4)N=CN=3)C=2)=O)C=1)(C)(C)C.O[C@H]1CCN(C(OC(C)(C)C)=O)C1.[C:47]([C:51]1[O:55][N:54]=[C:53]([NH:56][C:57](=[O:91])[NH:58][C:59]2[CH:60]=[C:61]([CH:88]=[CH:89][CH:90]=2)[O:62][C:63]2[C:72]3[C:67](=[CH:68][C:69]([O:75][C@H:76]4[CH2:80][CH2:79][N:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77]4)=[C:70]([O:73][CH3:74])[CH:71]=3)[N:66]=[CH:65][N:64]=2)[CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>>[C:47]([C:51]1[O:55][N:54]=[C:53]([NH:56][C:57](=[O:91])[NH:58][C:59]2[CH:60]=[C:61]([CH:88]=[CH:89][CH:90]=2)[O:62][C:63]2[C:72]3[C:67](=[CH:68][C:69]([O:75][C@@H:76]4[CH2:80][CH2:79][N:78]([C:81]([O:83][C:84]([CH3:86])([CH3:85])[CH3:87])=[O:82])[CH2:77]4)=[C:70]([O:73][CH3:74])[CH:71]=3)[N:66]=[CH:65][N:64]=2)[CH:52]=1)([CH3:48])([CH3:49])[CH3:50]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 23 %

Procedure:
Prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea from Example 95B (350 mg, 0.780 mmol) and (S)-3-hydroxy-1-tert-butoxycarbonylpyrrolidine (219 mg, 1.17 mmol) according to the procedure described for (S)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate in Example 96A to afford (R)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate as a colorless oil (109 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.00 (brs, 1H), 8.57 (s, 1H), 7.50-7.70 (m, 2H), 7.40-7.50 (m, 2H), 7.30 (m, 1H), 7.00 (m, 1H), 6.48 (s, 1H), 5.30 (brs, 1H), 4.00 (s, 3H), 3.70 (m, 1H), 3.40-3.50 (m, 2H), 3.25 (m, 1H), 2.20-2.40 (m, 2H), 1.40 (s, 9H), 1.30 (s, 9H); LC-MS (ESI) m/z 619 (M+H)+.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([O:13][CH:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28](OCC)OCC)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]>C(Cl)(Cl)Cl>[CH2:11]([O:13][CH:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[NH:10][C:1](=[O:9])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[O:4]2)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]
Reactant: CCOC(COc1ccc(CC(OCC)C(=O)OC)cc1)OCC
Reactant: NC(=O)c1ccccc1O
Solvent: ClC(Cl)Cl
Product: CCOC(Cc1ccc(OCC2NC(=O)c3ccccc3O2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a stirred solution of polyphosphonate ethyl ester (PPE) (3.46 g, 8.0 mmol) in chloroform (10 mL) was added salicylamide (548 mg, 4.0 mmol) followed by addition of a solution of (±)-Methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (1.28 g, 4.4 mmol) obtained in preparation 2, in chloroform (10 mL) dropwise at 25-30° C. The reaction mixture was immersed in a preheated oil bath at 70° C. and refluxed 12 h. The reaction mixture was cooled to room temperature and CHCl3 was removed under reduced pressure. The resultant residue was neutralised (pH=7.0) with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was chromatographed on silica gel using a gradient of 5-25% of ethyl acetate in pet ether as eluent to afford the title compound (1.15 g, 72%) as a pale yellow liquid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl.Cl>[CH3:12][O:11][C:8]1[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1CCOC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [6-methoxy-2′-(2-oxo-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.117 g, 0.28 mmol) in THF (1.2 mL) and MeOH (0.9 mL) was added 1N aqueous NaOH (0.61 mL), and the reaction was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and aqueous HCl. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. M+H is 410.
Reaction SMILES: [F:1][C@@H:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.S(C1C=CC(C)=CC=1)(O[CH2:38][C@@H:39]([O:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][O:47]1)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=O)=O>O>[F:1][C@@H:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:38][C@@H:39]([O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:14][CH:13]=2)=[N:8][CH:7]=1
Reactant: CCCC[C@H](F)CCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCC[C@@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC[C@@H](COc1ccc(-c2ncc(OCC[C@@H](F)CCCC)cn2)cc1)OC1CCCCO1
Yield: 110.7 %

Procedure:
In a reaction flask were charged 3.5 g of 5-[3-(S)-fluoroheptyloxy]-2-(4-hydroxyphenyl)pyrimidine synthesized in the same manner as in steps 1 to 7 of Example 1, 3.17 g of potassium carbonate, 70 ml of DMF, and 6.4 g of 2-(S)-tetrahydropyranyloxyheptyl tosylate in a nitrogen stream, and the mixture was allowed to react at 80° C. for one day. After cooling, water was added thereto, the reaction mixture was extracted with toluene, and the solvent was removed from the extract to obtain 7.6 g of a crude product. Purification by silica gel column chromatography gave 6.4 g of the titled compound.
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CN1c2c(C#N)cc(Cc3ccc(F)cc3F)cc2[C@@H]2CNCC[C@@H]21

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (20 mg, 59%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), 2,4-difluoro-benzylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 340 (base, M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][NH:34][CH2:33]2)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]2[CH2:36][CH2:35][N:34]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:33]2)=[CH:30][CH:31]=1
Reactant: Clc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-(4-chlorophenyl)pyrrolidine oxalate (16.3 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.4 mg). Calcd for C21H16ClF3N2O2: 420.0852, found 420.0855.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[O:20][N:19]=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2nc(CCl)no2)cc1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: COc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[4-(methyloxy)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 399 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:24])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]1[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]2[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]2([CH3:21])[CH3:20])[NH:3][N:2]=1)=[O:24])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCC1C(C)CCCC1(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCC2C(C)CCCC2(C)C)[nH]n1
Yield: 31.7 %

Procedure:
Hydrazine hydrate (0.867 mL, 17.9 mmol) was added to a stirring room temperature solution of 52 (5.2981 g, 17.9 mmol) in EtOH (17.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 97:3 Hexanes:2N NH3 in EtOH) to obtain 1.6604 g (31.8%) of 53. Partial 1H (CDCl3, 400 MHz): δ 12.45 (1H, broad s), 6.58 (1H, s), 4.32 (2H, q, J=7.1 Hz), 2.63 (2H, t, J=8.3 Hz), 1.31 (3H, t, J=7.1 Hz), 0.90 (3H, s), 0.83 (3H, s), 0.78 (3H, d, J=6.8 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 106.04, 60.66, 48.99, 34.03, 30.10, 24.89, 14.17 ppm. HPLC: 12.000 min.
Reaction SMILES: [N:1]([C@@H:4]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-]>[Pd].C(OCC)(=O)C>[Si:7]([O:6][CH2:5][C@H:4]([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[NH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9]
Reactant: Cc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reaction time: 1 h

Procedure:
A mixture of (S)-5-(1-azido-2-(tert-butyldimethylsilyloxy)ethyl)-2-methylpyridine (11.21 g, 0.036 mol), ethyl acetate (400 mL), and 10% Pd—C (7 g) was stirred under H2 (1 atm) for 1 hour. The catalyst was filtered off and the filtrate was concentrated to get the title product as an oil. 1H NMR (CD3OD, 400 MHz): 8.39 (d, 1H, J=2.0 Hz), 7.74 (dd, 1H, J=8.0, 2.4 Hz), 7.28 (d, J=8.0 Hz, 1H), 3.98 (t, 1H, J=6.0 Hz), 3.73 (d, 2H, J=6.0 Hz), 2.51 (s, 3H), 0.86 (s, 9H), −0.02 (s, 6H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[C:24]2=[C:25]3[C:13]([N:14]([Si](C(C)(C)C)(C)C)[CH:15]=[C:16]3[CH2:17][C@@H:18]3[C:23]2=[CH:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:20][N:19]3[CH3:34])=[CH:12][CH:11]=1>>[Cl:1][C:11]1[CH:12]=[C:13]2[C:25]3[CH:16]([CH2:17][C@@H:18]4[C@@H:23]([C:24]=3[CH:10]=1)[CH2:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:20][N:19]4[CH3:34])[CH2:15][NH:14]2
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Reactant: O=C1CCC(=O)N1Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Cl)cc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With N-chlorosuccinimide and 3-(12-bromo-1-tert-butyldimethylsilyl-9,10-didehydro-6-methyl-8α-ergolinyl)1,1-diethylurea:
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[C:22]([C@@H:34]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:35][CH2:36][N:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH:21]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:50])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C@@H:34]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:35][CH2:36][N:37]([CH:38]([CH3:39])[CH3:40])[CH:41]([CH3:43])[CH3:42])[CH:21]=2)=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(/C=C/COc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1OCc1ccccc1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1O)C(C)C
Temperature: 25 °C

Procedure:
tert-Butyl[2-(4-{[(2E)-3-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}prop-2-en-1-yl]oxy}phenyl)ethyl]carbamate (Preparation 6, 475 mg, 0.70 mmol) was dissolved in ethanol (20 ml) and 10% palladium on carbon (50 mg) added. The reaction was heated to 40° C. under 50 psi of hydrogen for 4 hours. The reaction was cooled to room temperature and filtered through Arbocel™, the filtrate was collected and the solvent removed in vacuo to furnish the title compound as a glass, 400 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)cnc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 8.3 grams (0.063 mole) of 2-amino-3-cyano-4-methylpyridine in 125 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide is added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. After this time, the reaction mixture is poured into 1 liter of aqueous 3N sodium hydroxide. The mixture is then diluted to a volume of about 1700 mL with distilled water. A solid precipitate is collected by filtration and dried under reduced pressure, yielding 2-amino-5-bromo-3-cyano-4-methylpyridine.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([N:30]=[CH:31][N:32]([CH3:34])[CH3:33])=[N:27][CH:26]=1)[CH:20]([NH:35]C(OC(C)(C)C)=O)[C:19]2=[O:43])=[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.CS(O)(=O)=O.C(OCC)(=O)C>C(#N)C>[NH2:35][CH:20]1[C:19](=[O:43])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([C:25]1[S:29][C:28]([N:30]=[CH:31][N:32]([CH3:34])[CH3:33])=[N:27][CH:26]=1)=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: CN(C)C=Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C=Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Yield: 100.7 %

Procedure:
Following the working method described in Example 15, 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylaminomethyleneamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form) (0.77 g) is treated with methanesulphonic acid (0.8 cc) in acetonitrile (8 cc). 7-Amino-2-benzhydryloxycarbonyl-3-(2-dimethylaminomethyleneamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form) (0.65 g) is obtained in the form of a crude brown froth (Rf=0.1, silica gel chromatographic plate; eluant: ethyl acetate), and this is redissolved in tetrahydrofuran (15 cc) and acylated, in accordance with the working method described in Example 1, with (thien-2-yl)acetyl chloride (0.15 cc) in the presence of triethylamine (0.17 cc). Chromatography is effected on a column (height: 28 cm; diameter: 2 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.8 bar (80 kPa) by means of ethyl acetate, and 30 cc fractions being collected. Fractions 11 to 19, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-3-(2-dimethylaminomethyleneamino-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0-oct-2-ene (E-form) (0.13 g) is obtained in the form of a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH:5]=[C:4]([N+:18]([O-])=O)[C:3]=1[O:21][C:22]1[C:27]([N+:28]([O-])=O)=[CH:26][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])=[CH:24][C:23]=1[Cl:41].[H][H]>C(O)C.O=[Pt]=O>[NH2:18][C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:16])([F:17])[F:15])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:21][C:22]1[C:23]([Cl:41])=[CH:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])=[CH:26][C:27]=1[NH2:28]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2C(F)(F)F)cc(Cl)c1Oc1c(Cl)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1cc(-c2ccccc2C(F)(F)F)cc(Cl)c1Oc1c(N)cc(-c2ccccc2C(F)(F)F)cc1Cl
Yield: 35.8 %

Procedure:
A solution of 2-chloro-α,α,α-trifluoro-6-nitro-p-tolylphenyl ether (150 g., 0.472 mole) in ethanol (1200 ml.) was shaken in an atmosphere of hydrogen in a Parr apparatus in the presence of PtO2 (600 mg.) until uptake ceased. The catalyst was filtered off, the solvent removed, and the residue taken up in pentane (600 ml.) and filtered through activated silica gel (~15 g.) and the solvent removed. The residue was recrystallized from pentane at -20° C. to give 2-amino-6-chloro-α,α,α-trifluoro-p-tolylphenyl ether (94.1 g., 70%) m.p. 47°-53° C.
Reaction SMILES: CC(C)N=C=NC(C)C.[CH:10]1[C:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[C:12]([N:22]([CH2:26][CH2:27][Cl:28])[CH2:23][CH2:24][Cl:25])[CH:11]=1.[CH3:29][CH:30]([CH2:32][CH2:33][CH2:34][C@H:35]([C@@H:37]1[C@:55]2([CH3:56])[C@H:40]([C@H:41]3[C@H:52]([CH2:53][CH2:54]2)[C@:50]2([CH3:51])[C:44]([CH2:45][C@H:46]([CH2:48][CH2:49]2)[OH:47])=[CH:43][CH2:42]3)[CH2:39][CH2:38]1)[CH3:36])[CH3:31].C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:31][CH:30]([CH2:32][CH2:33][CH2:34][C@H:35]([C@@H:37]1[C@:55]2([CH3:56])[C@H:40]([C@H:41]3[C@H:52]([CH2:53][CH2:54]2)[C@:50]2([CH3:51])[C:44]([CH2:45][C@H:46]([CH2:48][CH2:49]2)[OH:47])=[CH:43][CH2:42]3)[CH2:39][CH2:38]1)[CH3:36])[CH3:29].[Cl:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][Cl:28])[C:12]1[CH:11]=[CH:10][C:15]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C([O-])CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DIC (170 μl, 1.10 mmol) was added to a solution of chlorambucil (669 mg, 2.20 mmol) in dry dichloromethane (15 ml). The mixture was stirred at room temperature for 0.5 hour and added to a solution of cholesterol (387 mg, 1.00 mmol) and DMAP (122 mg, 1.00 mmol) in dichloromethane (10 ml). The reaction mixture was stirred overnight and then poured onto 5% sodium bicarbonate. The phases were separated and the organic phase was washed with brine and dried (MgSO4). The solution was filtered and concentrated and the product was purified by column chromatography (silica, chloroform) to give 560 mg (83%)of colouless oil. The product was characterised by MALDI mass spectrometry, giving M+H at 674 as expected. Further characterisation was carried out using 1H (500 MHz) and 13C (125 MHz) NMR analysis, giving spectra in accordance with the structure.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[N:13]1([CH2:19][CH2:20][OH:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCOCC>C(Cl)Cl>[N:3]1([C:1]([O:21][CH2:20][CH2:19][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCCN1CCOCC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCCN1CCOCC1)n1ccnc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.9 %

Procedure:
A mixture of 1,1′-carbonyldiimidazole (6.5 g, 40 mmol) and 2-(4-morpholinyl)-1-ethanol (5.0 g, 38.1 mmol) in DCM (200 mL) was stirred for 22 h at rt. Ether (400 mL) was added and the mixture was washed with water. The water layer was then extracted with DCM. The combined organic layers were dried over Na2SO4 and evaporated to give 6.0 g (70%) of the tide compound.