Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(C)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]O)=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].[OH-].[Na+]>O1CCCC1.CN(C)C=O.O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][N:28]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:29])=[CH:11][CH:12]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Mesyl chloride (2.10 ml, 27.1 mmol) was added to a solution of 3-(4-chlorophenyl)propyl alcohol (4.6 g, 27 mmol) obtained in 1) above and triethylamine (3.78 ml, 27.1 mmol) in tetrahydrofuran (100 ml) at 0° C. and stirred at room temperature for 30 minutes. Water was added to the reaction mixture which was then extracted with ethyl acetate. The extract was washed with an aqueous saturated NaCl solution and dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the reaction mixture and potassium phthalimide (5.02 g, 27.1 mmol) were dissolved in dimethylformamide and heated at 80° C. for 10 hours under stirring. 8 N aqueous sodium hydroxide was added to the resultant solution which was then extracted with ethyl acetate. The extract was washed with an aqueous saturated NaCl solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, whereby 7.47 g 2-[3-(4-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione was obtained as solid.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:28]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:23])[CH2:15][O:16]C2CCCCO2)[CH2:5][C@@H:4]([OH:31])[CH2:3]1.C(O)(=O)C>O>[CH3:23][C@@H:14]([C@@H:13]1[C@:24]2([CH3:30])[C@H:10]([C@H:9]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:29])[C:6]([CH2:5][C@@H:4]([OH:31])[CH2:3][C@@H:2]2[OH:1])=[CH:7][CH2:8]3)[CH2:11][CH2:12]1)[CH2:15][OH:16]
Reactant: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
A solution of 0.69 g. of (20S)-1α,3β-dihydroxy-20-methyl-21-tetrahydropyranyloxypregna-5-ene in 6.9 ml. of acetic acid and 2.1 ml. of water was warmed to 80° and an additional 3.2 ml. of water was added. The mixture was kept at 80° for one hour, cooled and poured into water. The suspension was extracted with ethyl acetate and the organic solution was washed with saturated sodium bicarbonate solution and water. After drying and evaporation under vacuum, 0.6 g. of (20S)-20-methyl-1α,3β,21-trihydroxypregna-5-ene was obtained. Recrystallization from acetone gave 0.3 g. of colorless prisms, m.p. 208°-209°; [α]D =-29° (c=0.5, methanol).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[CH:15][N+:12]([O-:14])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(F)c(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(F)c(C=C[N+](=O)[O-])c1
Yield: 97.4 %

Procedure:
Heat 2-fluoro-5-methoxybenzaldehyde (15 g, 97.4 mmol) with nitromethane (32 mL, 584 mmol) and ammonium acetate (30 g, 390 mmol) in acetic acid (136 mL) under reflux for 30 min. Evaporate the solvent and dissolve the residue in ether. Wash the organic fraction with water, saturated aqueous NaHCO3 and evaporate to give the desired intermediate (18.7 g, 97%). GC-MS m/z: 197 (M)+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[H-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][C:25]([O:29][CH3:30])([O:27][CH3:28])[CH3:26])[C:16]=1[F:31]>CN(C=O)C>[CH3:30][O:29][C:25]([O:27][CH3:28])([CH3:26])[CH2:24][C:17]1[C:16]([F:31])=[C:15]([N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(F)c1F)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(Cc1c([N+](=O)[O-])ccc(N2C(=O)c3ccccc3C2=O)c1F)OC
Temperature: 100 °C
Yield: 62.7 %

Procedure:
To a solution of phthalimide (4.4 g; 30 mmol) in anhydrous DMF (40 ml) cooled to 0° C. was added sodium hydride (1.29 g, 32 mmol, 60% in oil). The mixture was stirred at this temperature for 30 minutes before the addition of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (6 g, 23 mmol), (prepared as described for the starting material in Example 11). The reaction mixture was heated at 100° C. for 3 hours under argon. Upon cooling to ambient temperature, the reaction mixture was poured over ice/water (200 ml) and the formed precipitate was collected by filtration and washed with water and ether. The solid was purified by flash chromatography using methylene chloride/methanol (99/1). Evaporation of the solvent gave 2-(2,2-dimethoxypropyl)-3-fluoro-4-phthalimidonitrobenzene (5.6 g, 63%) as a yellow solid.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[CH3:11][CH:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]([C:18](OC)=[O:19])[C:14](OC)=[O:15]>CO.C1(C)C=CC=CC=1>[OH:19][C:18]1[C:13]([CH:12]([CH3:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:14]([OH:15])[N:10]=[CH:8][N:9]=1
Reactant: N=CN
Reactant: COC(=O)CC(C)C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC(C)c1c(O)ncnc1O
Temperature: 3.0999999046325684 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
A 12-L, 4-necked reactor, equipped with a mechanical stirrer, was charged with 2.80 L of methanol and sparged with nitrogen. The solvent was treated with NaOMe (1969 mL, 8612 mmol) and transfer washed with 250 mL of methanol. The mixture was left to stir for 1.5 hours before the solution was treated with formamidine acetate (246.6 g, 2368 mmol) in one sum (granular-homogenized). The mixture was allowed to stir for 20 minutes (the solids dissolved within about 10 minutes post addition) to afford a homogeneous solution. Trimethyl 2-methylpropane-1,1,3-tricarboxylate (500 g, 2153 mmol) was added via dropping funnel as a solution in 500 mL of methanol over a five minute period, followed by 200 mL more of methanol to complete transfer. The reaction (clear, bright yellow) was allowed to stir at ambient temperature overnight to completion as measured by NMR analysis (alliquot of 250 uL was removed via pipet and treated with five drops of aq. 3N HCl, reduced under vacuum to dryness, dissolved in d6-DMSO and then filtered) after 16 hours. The reaction was placed in an ice-bath and cooled to about 3.1° C. over a one hour period. A three-pound bottle of HCl (g) was used to quench the reaction (bubbling gas into solution via teflon tubing) over a one hour ten minute period reaching an endpoint of about pH=2.5 (via paper). The temperature was maintained below about 9.6° C. throughout the addition, and the yellow solution changed to an off-white suspension. The suspension was concentrated using vacuum distillation (35-37° C. @ 200 Torr) of the methanol (removed 3.34 L) in vacuo to afford a white/tan paste. The mixture was suspended in 3.75 L of toluene (7.5× volume) and stirred for 30 minutes. The suspension was filtered off (table top filter/polypropylene cloth, pad washed with 2×500 mL portions of toluene). The pad of product was allowed to air-dry under suction overnight on the filter then broken up with a spatula to give 396.8 grams, 86.9% yield.
Reaction SMILES: [CH3:1][C:2]1([CH:5]=O)[CH2:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:17][NH2:18].[BH4-].[Na+]>CO>[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]([O:19][Si:20]([CH2:21][CH3:22])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:17][NH:18][CH2:5][C:2]1([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C=O)CC1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[Si](CC)(CC)OC(CNCC1(C)CC1)c1c(Cl)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A mixture of 1-methylcyclopropanecarbaldehyde (31.6 mg, 0.375 mmol) and 2-(2,6-dichloro-4-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine (127 mg, 0.375 mmol) in MeOH (1.9 ml) was stirred at room temperature for 3 h. NaBH4 (14.20 mg, 0.375 mmol) was added in portions and the mixture was stirred at room temperature for 40 min. The mixture was concentrated and purified by prep TLC eluted with 5% MeOH/DCM to provide 2-(2,6-dichloro-4-fluorophenyl)-N-((1-methylcyclopropyl)methyl)-2-((triethylsilyl)oxy)ethanamine (111 mg, 0.273 mmol, 72.8% yield). 1H NMR (500 MHz, CDCl3) δ 7.29 (s, 1H), 7.06-7.10 (m, 2H), 5.56 (br. s., 1H), 3.33 (t, J=10.51 Hz, 1H), 2.81 (d, J=9.17 Hz, 1H), 2.60-2.67 (m, 1H), 2.44 (d, J=11.86 Hz, 1H), 1.46-1.59 (m, 1H), 1.13 (s, 3H), 0.85-0.96 (m, 9H), 0.50-0.63 (m, 6H), 0.36 (br. s., 2H), 0.30 (br. s., 2H); LCMS (ESI) m/z 406.0 (M+H)+.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Si:13](Cl)([CH3:16])([CH3:15])[CH3:14].[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[O:43])[CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:25]=2)[O:20]1>C1COCC1.C(OCC)C>[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]([O:43][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:25]=2)[O:20]1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(C=C(O[Si](C)(C)C)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 74 %

Procedure:
i-Pr2NH (0.556 mL, 4.04 mmol), distilled from CaH, was added to THF (7 mL) and cooled to −78° C. A solution of n-BuLi (2.59 M in THF, 1.56 mL, 4.04 mmol) was added dropwise. After completion of addition the reaction mixture stirred at −30° C. for 35 minutes and then cooled down again to −78° C. TMS-Cl (0.546 mL) and 1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (1.20 g, 3.23 mmol) dissolved in THF (25 mL) were added dropwise to the stirring reaction mixture. After completion of addition the reaction mixture continued stirring at −78° C. for an additional 30 minutes before being warmed up to −30° C. After stirring at −30° C. for 1 hour the reaction was diluted with diethyl ether and warmed to room temperature. At room temperature the reaction mixture was concentrated and the resulting crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate to 1:1 pentane:ethyl acetate) to obtain the desired compound (879.1 mg, 74% yield based on recovered starting material).
Reaction SMILES: [CH3:1]N(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:1])=[C:9]([O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH:8]=1
Reactant: CN(C)C=O
Reactant: Oc1ccc(Br)cc1OC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(Br)cc1OC1CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To 60 ml of N,N-dimethylformamide solution containing 6.22 g (25.6 mmol) of 4-bromo-2-cyclobutoxyphenol obtained in Reference Example 5-(d) were successively added 3.54 g of potassium carbonate and 3.2 ml of methyl iodide, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene), and the obtained crude solid was recrystallized from hexane to obtain 3.90 g of the title compound as a colorless solid. (Yield: 59%)
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:27])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.3 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(2-methylpropanoyl)thiophen-3-yl]methyl}amino)benzoic acid (139 mg) synthesized in Example 287 (8), ethyl 3-(methylamino)propanoate (53.0 mg), 1-hydroxybenzotriazole monohydrate (61.9 mg) and triethylamine (56 μL) in N,N-dimethylformamide (10 mL) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77.4 mg) was added, and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane), and then purified by NH-silica gel column chromatography (ethyl acetate) to give a colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (101 mg, 60%) as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][NH:12][C:13]([C:15]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([F:34])[C:18]2[N:19]=[CH:20][N:21]([CH3:22])[C:17]=2[CH:16]=1)=[O:14])C)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[OH:40][C:38]([C:37]([F:42])([F:41])[F:36])=[O:39].[CH3:6][NH:7][CH2:9][CH2:10][O:11][NH:12][C:13]([C:15]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([F:34])[C:18]2[N:19]=[CH:20][N:21]([CH3:22])[C:17]=2[CH:16]=1)=[O:14]
Reactant: CN(CCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
Prepared from (2-{[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbonyl]-aminooxy}-ethyl)-methyl-carbamic acid tert-butyl ester 29ww by trifluoroacetic acid deprotection in methylene chloride. MS APCI (+) m/z 470, 472 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.74 (s, 1H), 7.51 (d, 1H), 7.19 (dd, 1H), 6.39 (dd, 1H), 4.11 (m, 2H), 3.97 (s, 3H), 3.12 (m, 2H), 2.72 (s, 3H); 19F NMR (376 MHz, CD3OD) −77.41 (s, 3F), −134.79 (s, 1F).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O>[CH2:30]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)[CH3:31]
Reactant: CCI
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 63.9 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.27 g), dimethylformamide (25 ml), and ethyl iodide (0.87 g), the title compound (0.69 g) was obtained as a crystalline solid, m.p. 180-183° C.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>>[Cl:1][C:2]1[N:11]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: ClCc1ccccc1Cl
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Cl)n(C)c1=O

Procedure:
From 8-Chorotheophylline (10 g, 47 mmol)) and 2-chlorobenzyl chloride (19.4 ml, 153.9 mmol). The 2-chlorobenzyl chloride was added in three portions. First third at reaction start as described in general procedure (E), and the other thirds after 24 and 48 hours respectively as the reaction had not completed. Total reaction time 7 days at RT. Due to incomplete precipitation in water the product was extracted with DCM (700 and 300 ml), dried (MgSO4), and evaporated to dryness in vacuo. Excess 2-chlorobenzyl bromide was removed by washing the product in Et2O.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[ClH:36].CO>O1CCOCC1>[ClH:36].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C2CCNCC2)c1
Reaction time: 18 h

Procedure:
A suspension of 1,1-dimethylethyl 4-(5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)-1-piperidinecarboxylate Example 115) (0.01 g) in a solution of hydrogen chloride in dioxan (4M, 1 ml) was treated with methanol (0.25 ml) to give a solution which was stirred at room temp. for 18 h. The solvent was evaporated and the residue was dried under vacuum to give the title compound (0.009 g).
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[NH2:21][CH2:22][CH2:23][NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CO.[Pt]>[OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:21][CH2:22][CH2:23][NH:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:6][CH2:5]1
Reactant: COc1ccccc1OCC(O)CN1CCC(=O)CC1
Reactant: NCCNC1CCNCC1
Agent: [Pt]
Solvent: CO
Product: COc1ccccc1OCC(O)CN1CCC(NCCNc2ccncc2)CC1

Procedure:
A solution of 27.9 g of 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-piperidin-4-one and 22.8 g of 4-(2-aminoethylamino)-piperidine in 250 ml of methanol, with the addition of 2 g of a platinum on charcoal catalyst, is hydrogenated at room temperature and under normal pressure until 1 molar equivalent has been taken up. The catalyst is thereafter removed by filtration and the filtrate is concentrated under reduced pressure. The residue is dissolved in 500 ml of methylene chloride and the solution is washed with three 150 ml portions of water, dried over sodium sulphate and concentrated under reduced pressure to yield 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-pyridyl-amino)-ethylamino]-piperidine, which can be processed without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:26]1[CH:27]=[CH:28][C:23]([CH:21]=[CH:22][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C=Cc2ccncc2)c1
Yield: 68.9 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 54b (1.03 g, 3.0 mmol) in acetonitrile (20 mL) and triethylamine (12.5 mL) was added 4-vinylpyridine (0.65 mL, 6 mmol), palladium acetate (125 mg, 0.56 mmol) and tri-o-tolylphosphine (625 mg). The mixture was heated at reflux for 16 hours. The solvent was removed, and the residue was washed with saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 1:2 to 0:1 to afford the title compound (760 mg, 69%). MS (CI/NH3) m/z 368 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.43 (s, 9H), 2.35 (m, 2H), 3.90 (m, 2H), 4.20 (m, 1H), 4.40 (m, 1H), 4.55 (m, 1H), 7.10 (m, 1H), 7.2 (m, 1H), 7.38 (m, 2H), 7.45 (br s, 1H), 8.29 (m, 1H), 8.37 (s, 1H), 8.61 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([OH:29])=O)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[CH3:36][NH2:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](=[O:29])[NH:37][CH3:36])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CN
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 33.8 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (2 g, 3.6 mmol) was reacted with methanamine hydrochloride (0.49 g, 7.2 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (0.69 g, 34%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:37])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M91) (0.36 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (250 mg, 88%).