Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][C:12]([NH:14][CH:15]2[C:40](=[O:41])[N:17]3[C:18]([C:24]([O:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[C:19]([CH2:22]O)[CH2:20][S:21][C@H:16]23)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[C:43]1([P:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.C(OCC)(=O)C>[Br-:2].[CH:27]([O:26][C:24]([C:18]1[N:17]2[C:40](=[O:41])[CH:15]([NH:14][C:12](=[O:13])[CH2:11][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C@H:16]2[S:21][CH2:20][C:19]=1[CH2:22][P+:49]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:25])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [Br-]
Reaction time: 0.25 h
Yield: 147 %

Procedure:
A solution of phosphorus tribromide (5.0 g) in tetrahydrofuran (10 ml) was dropwise added to a mixture of benzhydryl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate (25.7 g) in tetrahydrofuran (200 ml) at -10° to -5° C. and the mixture was stirred at the same temperature for 15 minutes. The resultant mixture was poured into a mixture of water (250 ml) and ethyl acetate (300 ml). The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated to give the oily product. The crude oily product was dissolved in ethyl acetate (250 ml) and triphenylphosphine (21 g) was added. The mixture was stirred at ambient temperature for 3 hours. The precipitate was collected by filtration and washed with ethyl acetate to give (4-benzhydryloxycarbonyl-7-phenylacetamido-3-cephem-3-ylmethyl)triphenyl phosphonium bromide (22.8 g).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[NH2:12][CH2:13][C:14]([O:16]C)=[O:15].S1C=CC=[CH:19]1.C([O-])=O.[Na+]>CO.[Pd]>[CH3:19][N:12]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH3:1])[CH2:3]1)[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CN
Reactant: CC1CC(=O)c2ccccc21
Reactant: c1ccsc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1CC(N(C)CC(=O)O)c2ccccc21
Yield: 54.1 %

Procedure:
A mixture of 21 parts of 2,3-dihydro-3-methyl-1H-inden-1-one, 25 parts of methyl 2-aminoacetate, 2 parts of a solution of thiophene in methanol 4%, 25 parts of sodium formate and 480 parts of methanol is hydrogenated in a Parr-apparatus and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. The reaction mixture is evaporated. The residue is taken up in water and 1,1'-oxybisethane is added. The separated organic layer is extracted with a hydrochloric acid solution 10%. The aqueous layer is made alkaline and the product is extracted with 1,1'-oxybisethane. The combined extracts are dried, filtered and evaporated, yielding 19 parts (54.1%) of methyl N-(2,3-dihydro-3-methyl-1H-inden-1-yl)glycine as a residue.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)([CH3:13])[CH3:12])[CH:5]=1.[OH-].[Li+]>O1CCCC1.O>[OH:26][C@H:16]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:27])=[O:2]
Reactant: COC(=O)c1cccc(CC(C)(C)NCC(O)c2ccc(O)c(CO)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-2-methylpropyl}-benzoic acid methyl ester (preparation 139) (2.35 g, 6.32 mmol) and lithium hydroxide (303 mg, 12.64 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was stirred at room temperature for 3 days. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified with 1M hydrochloric acid (12 mL). The mixture was stirred for 2 hours at room temperature and was then concentrated in vacuo. The crude residue was used in subsequent reactions without further purification. 1H NMR (400 MHz, CD3OD) δ: 7.87 (1H, m), 7.84 (1H, bs), 7.39-7.31 (3H, m), 7.19 (1H, dd), 6.79 (1H, d), 4.86 (1H, m), 4.66 (2H, s), 3.22-3.11 (2H, m), 3.02 (2H, m), 1.32 (6H, s) ppm; LRMS ESI m/z 360 [M+H]+
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[N:41]=[C:40]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:62]>ClCCl>[CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:49])=[O:50])[N+:41]([O-:62])=[C:40]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCS(C)(=O)=O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCS(C)(=O)=O)[n+]1[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a dichloromethane solution (0.06 M) of tert-butyl (3-[cyclopropyl({2-(3-methoxypropyl)-6-[3-(methylsulfonyl)propoxy]pyridin-4-yl]methyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 101, Step 1 (1 eq.) was added 3-chloroperoxybenzoic acid (3.6 eq.). The resulting solution was stirred at RT for 18 h. The reaction was quenched with sat. aq. NaHCO3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 90:10 (v/v) CH2Cl2:EtOH→85:15 (v/v) CH2Cl2:EtOH) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:17]([CH2:18][Cl:19])=[N:16][C:15]([C:20](Cl)=[O:21])=[N:14]1)=[O:5].[CH2:27]([NH2:29])[CH3:28]>O1CCOCC1>[CH2:27]([NH:29][C:20]([C:15]1[N:16]=[C:17]([CH2:18][Cl:19])[N:13]([C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=2[C:4](=[O:5])[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[Cl:1])[N:14]=1)=[O:21])[CH3:28]
Reactant: CCN
Reactant: O=C(Cl)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Solvent: C1COCCO1
Product: CCNC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
The resulting crude 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carbonyl chloride is dissolved in 80 ml of dioxane, and to the solution is added dropwise at room temperature, in the course of 30 minutes, a solution of 1.98 g (0.044 mole) of ethylamine in 30 ml of dioxane. The ethylamine hydrochloride gradually precipitates out. The reaction mixture is concentrated in vacuo to dryness. Ice water and ether are added to the residue; the organic phase is separated and is washed successively with cold 1 N hydrochloric acid, with cold 0.1 N sodium hydroxide solution and with saturated sodium chloride solution. After drying, and concentration in vacuo, is obtained crude N-ethyl-1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>>[CH3:35][N:36]([CH3:46])[C:37]1[CH:42]=[C:41]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[CH:13]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(N(C)C)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-dimethylamino-phenylboronic acid under the conditions described in Example 1; 1H NMR (300 MHz, MeOD) δ ppm 0.99 (dd, J=6.59, 2.45 Hz, 6H), 1.58 (dt, J=13.28, 6.73 Hz, 1H), 1.78 (ddd, J=13.75, 7.16, 6.97 Hz, 1H), 2.03-2.13 (m, 1H), 3.32 (s, 6H), 3.88 (t, J=7.72 Hz, 1H), 7.49 (d, J=7.91 Hz, 1H), 7.68-7.83 (m, 7H), 7.86-7.94 (m, 3H); Calcd for C27H28F3NO2 (M+H) 456.21, Found 456.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]1[CH2:10][CH2:11][CH2:12][CH:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[C:8]1=[O:13]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1N1CCOCC1
Product: CN(C)C=C1CCCC(N2CCOCC2)C1=O

Procedure:
2-Morpholin-4-yl-cyclohexanone (183 mg, 1.0 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (260 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2cccnc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2cccnc12
Yield: 57.7 %

Procedure:
8-Methylquinoline (4.02 g) was dissolved in carbon tetrachloride (40 ml), and N-bromosuccinimide (5.98 g) and benzoyl peroxide (0.15 g) were added to the solution, and the mixture was heated and refluxed for 3 hours. After filtering off the insoluble matter, the filtrate was concentrated. The resultant residue was recrystallized from ligroin to give 8-bromomethylquinoline (3.60 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].CI.[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100 %

Procedure:
Step AH (1): To a solution of 2-bromo-5-hydroxybenzaldehyde (1000.0 mg, 4.975 mmol) in DMF (20 mL) were added methyl iodide (0.31 mL, 5.000 mmol) and potassium carbonate (1036.6 mg, 7.500 mmol). The reaction mixture was stirred at rt for 2.5 days. Water was added and the reaction mixture was extracted with hexanes-ether (1:1) solvent system. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum to yield 2-bromo-5-methoxybenzaldehyde (1069.8 mg, 100%) as colorless oil. LC-MS (M+H)+=215.11. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H). 7.70 (d, J=10 Hz, 1H) 7.35 (d, J=3 Hz, 1H) 7.23 (dt, J1=7.0 Hz, J2=2.0 Hz, 1H) 3.83 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:11]#N)[CH2:10][CH:9]=[CH:8][CH2:7]1.[OH-:13].[K+].C(O)C[OH:17]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:11]([OH:17])=[O:13])[CH2:10][CH:9]=[CH:8][CH2:7]1
Reactant: N#CC1(c2cccs2)CC=CC1
Reactant: [OH-]
Reactant: OCCO
Agent: [K+]
Product: O=C(O)C1(c2cccs2)CC=CC1

Procedure:
1-(2-Thienyl)cyclopent-3-en-1-carbonitrile and potassium hydroxide were reacted in ethylene glycol under heating to obtain 1-(2-thienyl)cyclopent-3-en-1-carboxylic acid.
Reaction SMILES: [Br:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[I:28])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:3](=[O:4])[C:2]([Br:1])([F:7])[F:6])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[I:28])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2I)CC1
Reactant: O=C(Cl)C(F)(F)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)C(F)(F)Br)c2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Bromodifluoroacetyl chloride (0.800 g, 4.1 mmol) was added dropwise to a cooled (0° C.) solution of 4-(2-Iodophenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.500 g, 3.7 mmol) and triethylamine (1.0 mL, 7.1 mmol) in dichloromethane (20 mL). The cooling bath was removed 30 minutes after the addition of all reagents. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. Purification of the residue by flash chromatography to afford 4-[(2-bromo-2,2-difluoroacetyl)-(2-iodophenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.730 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J=1.2 and 7.8 Hz, 1H), 7.41-7.06 (m, 3H), 4.45-4.37 (m, 1H), 4.17-4.03 (m, 2H), 2.81-2.64 (m, 2H), 2.18-2.12 (m, 1H), 1.89-1.84 (m, 1H), 1.59-1.52 (m, 1H), 1.40 (s, 9H), 1.25-0.98 (m, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:10](=[O:9])[CH2:11][NH2:16])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)CN)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in (100 mg) in dry methylene chloride (4 ml) was added 100 mg of freshly prepared BOC-L-glycine anhydride under nitrogen. After stirring at room temperature for 1.5 hours, the reaction mixture was subjected to work-up and the residue was purified on silica gel (5% MeOH/CH2Cl2) to give the 65 mg of BOC protected compound. This material (48 mg) was dissolved in 1 ml of trifluoroacetic acid at -10° and stirred at this temperature. After 30 minutes, the reaction mixture was cooled to -78° and freeze-dried to give the yellow solid. Purification of the crude material by preparative tlc on silica gel (1% NH4OH in 5% MeOH/CH2Cl2) gave 28 mg of the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH:21]=[CH:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH:21]=[CH:22][CH2:23]4)[C:18](=[O:25])[N:17]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1
Reactant: BrC1CCCC1
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 5 and cyclopentylbromide as described for compound 8. Crystallized from diethyl ether. M.p. 144-145° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[N:3]=1.[NH3:19].O1[CH2:25][CH2:24]OCC1>>[N:13]1([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:3]4[CH2:25][CH2:24][CH2:6][CH2:5][CH2:4]4)=[N:11][C:2]([NH2:19])=[N:3]3)=[CH:8][CH:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCO1
Reactant: Clc1nc(Cl)c2ccc(N3CCOCC3)cc2n1
Reactant: N
Product: Nc1nc(N2CCCCC2)c2ccc(N3CCOCC3)cc2n1

Procedure:
0.166 g (0.50 mmol) of 2,4-dichloro-7-morpholin-4-ylquinazoline and 1.0 ml of ammonia solution (32%) in 2.0 ml of dioxane were heated in a cem microwave at 130° C. (80 watts) for 150 min. Conventional work-up gave 0.04 g of 7-morpholin-4-yl-4-piperidin-1-ylquinazolin-2-ylamine (No. 57).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O>C(O)CCC>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:15]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol) in BuOH (20 mL) was added potassium tert-butoxide (4.125 g, 18.75 mmol). The mixture was stirred at 50° C. for 1 h. Then trimethyl sulfoxonium iodide (11 g, 50 mmol) was added to the mixture, and the resulting reaction mixture was stirred at 50° C. overnight. When TLC showed that s.m. was consumed, the mixture was cooled and filtered. The filtrate was concentrated to give the crude product which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+:26].[Na].O1CCCC1>CO.C(#N)C>[F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:26])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-fluoro-8-(3-fluorophenyl)quinolin-7-yl]ethanone (0.32 g, 1.1 mmol) and ammonium acetate (0.871 g, 11.3 mmol) in methanol (3.0 mL) and acetonitrile (3.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohyride in tetrahydrofuran (2.8 mL, 2.8 mmol). The reaction was heated at 65° C. overnight, then cooled to room temperature and quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined extracts were dried over MgSO4 and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C17H15F2N2 (M+H)+: m/z=285.1; Found: 285.1.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[CH2:24]([NH:26][CH3:27])[CH3:25]>>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]([CH2:24][CH3:25])[CH3:27])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=1
Reactant: CC(C)c1cccc(-c2c(C#N)c(Cl)nc3ccc(Cl)cc23)c1
Reactant: CCNC
Product: CCN(C)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C#N

Procedure:
The title compound was prepared in analogy to example 98 step E from 2,6-dichloro-4-(3-isopropyl-phenyl)-quinoline-3-carbonitrile (prepared as described in example 98 step D) and ethyl-methyl-amine. Light yellow oil. MS (ESI): 364.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:3]=1
Reactant: COc1cccc(CCl)c1
Reactant: Oc1ccc(F)cc1
Product: COc1cccc(Cc2cc(F)ccc2O)c1

Procedure:
Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3'-methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[CH:8]([C:14]1([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]1)[NH:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH:31]=[CH2:32].B(Br)(Br)[Br:35]>CC(C)=O.ClCCl.CO>[BrH:35].[CH2:32]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)[CH:8]1[C:14]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15]1)[CH:31]=[CH2:30]
Reactant: BrB(Br)Br
Reactant: C=CCI
Reactant: COc1cc2c(cc1Cl)CCNC2C1(c2ccccc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: Br
Product: C=CCN1CCc2cc(Cl)c(O)cc2C1C1(c2ccccc2)CCC1
Temperature: -70 °C

Procedure:
6-Chloro-7-methoxy-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline (1.38 g prepared in a similar manner to that described in Example 59) which was dissolved in acetone (50 ml) and stirred with anhydrous potassium carbonate (1.16 g) and allyl iodide (0.78 g) for one hour. The mixture was filtered and the filtrate concentrated and partitioned between water and ether. The ether layer yielded an oil which was taken up in dichloromethane (30 ml) and cooled to -70° C. A 1M solution of boron tribromide in dichloromethane (11 ml) was added dropwise and the mixture allowed to warm to ambient temperature. After two hours the mixture was cooled to -60° C. and methanol (30 ml) was added cautiously. The solvents were removed and the residue decolourised with charcoal in methanol. Removal of the solvent gave a residue which was recrystallised from a mixture of propan-2-ol and ether to give 2 -allyl-6-chloro-7-hydroxy-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 194°-196° C.