Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C1CCCCC1)C1CCCCC1.Br[C:16]1[C:17]([N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:23](=[O:41])[CH2:24][C:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH:30]=2)=[N:18][CH:19]=[CH:20][CH:21]=1>O1CCOCC1.O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:41]=[C:23]1[CH2:24][C:25]2([CH:26]=[CH:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH2:30]2)[C:16]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:22]1[CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)CC2(C=CN(C(=O)OCc3ccccc3)CC2)c2cccnc21
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To a mixture of N-methyldicyclohexylamine (0.042 mg, 0.20 mmol) and benzyl 4-[2-((3-bromopyridin-2-yl) {[2-(trimethylsilyl)ethoxy]methyl}amino)-2-oxoethyl]-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.178 mmol) in dioxane (2 mL) was added bis(tri-tert-butylphosphine) palladium(0) (9 mg, 0.018 mmol). After 5 min, the reaction was heated to 50° C. After 90 min, bis(tri-tert-butylphosphine) palladium(0) (9 mg) was added. After an additional 30 min at 50° C., the reaction mixture was diluted with water and extracted with ether (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 5 to 60% ethyl acetate:hexanes to give the title compound (68 mg). MS: m/z=480.2 (M+1).
Reaction SMILES: COC(=O)CNC(=O)C=CC1C=CC=CC=1.[C:17]([O:21][C:22](=[O:25])[CH2:23][NH2:24])([CH3:20])([CH3:19])[CH3:18].CN1CCOCC1.[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.ClC(OCC(C)C)=O>CN(C)C=O.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:25])[CH2:23][NH:24][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: COC(=O)CNC(=O)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CNC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Following the same general procedure described previously for cinnamoyl-glycine-methyl ester, glycine-t-butyl ester. MCl (10.88 grams) was dissolved in dimethyl formamide (approximately 100 ml), cooled to 0° C. and treated with N-methylmorpholine (9.04 ml, 1 equivalent) followed immediately by a pre-cooled solution of benzoic acid (7.94 grams) in ethyl acetate (approximately 75 ml) which had been pre-activated by treatment with N-methylmorpholine (9.04 ml) followed by isobutyl chloroformate (8.4 ml) at -20° C. After work-up, benzoyl-glycine-t-butyl ester was obtained as a white solid which was used for the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:11][C:12]([OH:14])=[O:13])[CH2:5][C:4](=[O:28])[O:3]1.C(N(CC)CC)C.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48]>CN(C)C=O>[C:19]([CH2:18][N:17]([CH2:16][CH2:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:6]([CH2:7][C:2](=[O:1])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:5][C:4]([OH:28])=[O:3])[CH2:22][C:23]([OH:25])=[O:24])([OH:21])=[O:20]
Reactant: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Reactant: NCCCCCCCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCCCCCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.33 g (38 mmol) of N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxy-carbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0331 616) is suspended in dimethylformamide (DMF) and mixed in an ice bath with 21.07 ml (152 mmol) of triethylamine and 7.65 g (38 mmol) of 11-aminoundecanoic acid. The temperature is allowed to increase to room temperature and the reaction solution is stirred overnight. After completion of the reaction, the possibly still slightly cloudy solution is filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is absorptively precipitated with ether and then recrystallized from water (17.8 g). The ethyl ester is dissolved in 2 N NaOH and is adjusted to pH 7 after 3 hours by adding Amberlite® IR 120 (H+). The ion exchange material is suctioned off, the filtrate is freeze-dried (20.1 g) and then added to H2O/methanol (2:1) on 100 ml of Amberlite® IR 120 (H+) and the acid eluate is concentrated by evaporation and recrystallized from water.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][CH2:22][C@H:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:17][CH:16]=1>>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][CH2:22][C@H:23]([N:28]2[CH2:29][CH2:30][N:31]([S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:32][CH2:33]2)[C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:17][CH:16]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCNCC2)cc1
Product: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(=O)(=O)C(C)C)CC2)cc1
Yield: 66.5 %

Procedure:
In a manner similar to example 2-1, starting from 0.2 ml (1.9 mmol) of 2-propanesulphonyl chloride and from 0.7 g (1.8 mmol) of methyl (S)-3-[4-(2-methoxy-ethoxymethoxy)benzoylamino]-2-piperazin-1-ylpropanoate, 0.6 g (68%) of methyl (S)-3-[4-(2-methoxyethoxy-methoxy)benzoylamino]-2-[4-(propane-2-sulphonyl)-piperazin-1-yl]propanoate is obtained in the form of a colourless oil.
Reaction SMILES: COC1C=C2C(=CC=1OCCOC)N=C[N:7]=C2OC1C=C(C=CC=1)N.[O:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:36]=[C:35]([NH:37][C:38](=[O:46])OC3C=CC=CC=3)[O:34][N:33]=2)[CH2:28][CH2:27]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[O:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:36]=[C:35]([NH:37][C:38](=[O:46])[NH2:7])[O:34][N:33]=2)[CH2:28][CH2:27]1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCOCC2)no1)Oc1ccccc1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: NC(=O)Nc1cc(C2CCOCC2)no1
Yield: 51.1 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (60 mg, 0.176 mmol) and phenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate from Example 123A (56 mg, 0.194 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 14346-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)urea as a colorless solid (19 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 10.70 (brs, 1H), 9.38 (brs, 1H), 8.55 (s, 1H), 7.57 (s, 2H), 7.38-7.42 (m, 2H), 7.32 (m, 1H), 6.98 (m, 1H), 6.00 (s, 1H), 4.34-4.35 (m, 2H), 3.99 (s, 3H), 3.87-3.90 (m, 2H), 3.77-3.78 (m, 2H), 3.42-3.46 (m, 2H), 3.35 (s, 3H), 2.88 (m, 1H), 1.76-1.81 (m, 2H), 1.60-1.65 (m, 2H); LC-MS (ESI) m/z 536 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[O:13]=[C:14]1[N:21]2[CH:16]([CH:17]([CH3:24])[CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH2:15]1.C(I)(C)C>CCCCCC.C1COCC1.CCOC(C)=O.CN(C)P(N(C)C)(N(C)C)=O>[O:13]=[C:14]1[N:21]2[CH:16]([CH:17]([CH3:24])[CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH:15]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC1COC(C)(C)N2C(=O)CC12
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CC(C)C1C(=O)N2C1C(C)COC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
THF, 20 ml, is placed under N2, treated with 1.54 ml diisopropylamine and cooled to -78° C. A solution of n-butyl lithium, 1.97 M in hexane (5.6 ml) is added dropwise over 5 min. The reaction mixture is stirred at -78° C. for 10 min and then treated with 8-oxo-2,2,5-trimethyl-3-oxa-1-azabicyclo[4.2.0]octane (1.55 g) in 15 ml THF which is added dropwise over 5 min. After another 10 min hexamethylphosphoramide (1.97 ml) is added. The mixture is stirred another 10 min, then treated with 2 ml of isopropyl iodide. The reaction mixture is stirred at -78° C. for 15 min and allowed to warm to 25° C. and stirred for 15 min. The reaction mixture is diluted with EtOAc, washed once with pH 7 phosphate buffer then dried and evaporated. The residue is chromatographed on silica gel using 25% EtOAc/C6H6 as eluant to give 8-oxo-2,2,5-trimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: CS([O:5][CH:6]1[CH:11]([CH3:12])[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:8][CH:7]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=O)=O.C(N(CC)CC)C.C[C:38]([O:41]C(OC(OC(C)(C)C)=O)=O)(C)C>N1C=CC=CC=1>[CH3:12][CH:11]1[CH:6]2[CH:7]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:38](=[O:41])[O:5]2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:10]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A solution of (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv.) in pyridine (0.2M) was heated in the microwave at 110° C. for 10 min. The orange reaction was then concentrated under vacuo, the crude was dissolved in ethyl acetate and water, the organic phase was dried with sodium sulfate and concentrated under vacuo. The crude material was dissolved in DCM (0.2M), triethylamine (1.8 equiv.) was added, followed by Boc2O (1.2 equiv.). The reaction was stirred for 40 min, then concentrated to dryness. The crude material was purified via silica gel column chromatography eluting with hexane and ethyl acetate (1:1) to afford (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate as a white foam in 66% yield. LC/MS=376.0 (M+H), LC: 3.424 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH3:26])[C@H:8]([C:10](=[O:25])[NH:11][C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:15]=2[O:14][CH2:13]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+].[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([CH2:47]Cl)=[C:42]([O:49][CH3:50])[CH:41]=[CH:40]2>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[N:7]([C@H:8]([C:10](=[O:25])[NH:11][C@@H:12]1[C:18](=[O:19])[N:17]([CH2:47][C:43]2[C:44]3[C:39](=[CH:38][C:37]([Br:36])=[CH:46][CH:45]=3)[CH:40]=[CH:41][C:42]=2[O:49][CH3:50])[C:16]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:15]=2[O:14][CH2:13]1)[CH3:9])[CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Reactant: Cc1ccc2c(c1)OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2cc(C)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
A mixture of methyl-[(S)-1-((S)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (241 mg, 639 μmol, Eq: 1.00), NaI (95.7 mg, 639 μmol, Eq: 1.00), Cs2CO3 (312 mg, 958 μmol, Eq: 1.50), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (219 mg, 766 μmol, Eq: 1.20) in DMF (3 mL) was stirred at RT for 1 h and at 50° C. for 1 h. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. The resulting material was purified by silica gel chromatography to afford {(S)-1-[(S)-9-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (63 mg, 16%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24](=[O:54])[N:25]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[N:26]([CH2:29][C@H:30]([O:32][C:33](=[O:47])[CH2:34][N:35](C(OCC5C=CC=CC=5)=O)[CH3:36])[CH3:31])[C:27]=4[CH3:28])=[O:22])=[CH:16][C:15]=3[F:55])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>CCOC(C)=O.CO.[Pd]>[CH3:36][NH:35][CH2:34][C:33]([O:32][C@H:30]([CH3:31])[CH2:29][N:26]1[C:27]([CH3:28])=[C:23]([C:21](=[O:22])[NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[C:15]([F:55])[CH:16]=2)[C:24](=[O:54])[N:25]1[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:47]
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCC(=O)O[C@H](C)Cn1c(C)c(C(=O)Nc2ccc(Oc3ccnc4cc(OC)ccc34)c(F)c2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-1-(4-(4-(7-methoxyquinolin-4-yloxy)-3-fluorophenylcarbamoyl)-2,3-dihydro-5-methyl-3-oxo-2-phenylpyrazol-1-yl)propan-2-yl-2-(N-benzyloxycarbo-nyl-N-methylamino)acetate (1.404 g, 1.876 mmol) in a mixture of EtOAc (100 mL) and MeOH (100 mL) was added catalytic amount of Pd/C (10%, ˜55% w/w water content, 100 mg) under N2 atmosphere. The suspension was degassed under vacuum and then purged with H2. The reaction mixture was stirred at rt for 1 h under H2 balloon. The mixture was filtered and the residue was washed with MeOH (50 mL×3). The filtrate used for the next step immediately.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:13]/[C:14](/[C:17]([CH3:19])=O)=[N:15]\[OH:16].[ClH:20].COC(C)(C)C>C(O)(=O)C>[ClH:20].[CH3:13][C:14]1[N+:15]([O-:16])=[C:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][C:17]=1[CH3:19]
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 10 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Into a solution of 4-trifluoromethyl benzaldehyde (400.0 g, 2.3 mol) and 2,3-butanedione monoxime (212 g, 2.055 mol) in 800 mL of glacial acetic acid at 2–5° C., hydrogenchloride gas (250 g) is slowly bubbled for 1.5 hours. The mixture is stirred at the same temperature for 1 hour further. 3.75 L of t-butyl methyl ether are added while maintaining the temperature between 5–25° C. (first 400 mL addition is exothermic). The resulting suspension is stirred for 30 minutes, then cooled to 10° C. and the solids are collected by filtration. The filter cake is washed with 500 mL of t-butylmethyl ether, and dried at 55–60° C. (20 mbar) for 18 hours to afford 550 g (91% yield) of 4,5-dimethyl-2-[4-(trifluoromethyl)phenyl]-oxazole 3-oxide, hydrochloride salt: m.p. 182–184° C. (with decomposition).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CO>[CH:7]([N:10]([CH:11]([CH3:13])[CH3:12])[C:3](=[O:4])[CH:2]([Cl:1])[CH3:6])([CH3:9])[CH3:8]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)NC(C)C
Solvent: CO
Product: CC(Cl)C(=O)N(C(C)C)C(C)C

Procedure:
Reaction of 2-chloropropionylchloride with diisopropylamine under the experimental conditions of Example 16, gives the product; b.p. 87°-88° (0.1 mm); Rf=0.67 (methanol); IR (neat) νmax: 2960, 2920, 1650, 1475, 1450, 1370, 1340, 1210, 1040, 620 cm-1 ; Cl (Schoeninger) calculated %: 18.49--Found %: 18.43.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[Br:8].[C:9]([O-:12])(=[O:11])[CH3:10].[K+].O>CC(C)=O>[C:9]([O:12][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[Br:8])(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: BrCc1ccsc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCc1ccsc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A mixture of 2-bromo-3-methylthiophene (17.7 g), N-bromosuccinimide (17.7 g), 2,2'-azobis(isobutyronitrile) (0.32 g) and carbon tetrachloride (200 ml) was stirred for 4 hours under reflux. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-bromomethyl-2-bromothiophene (12.56 g). A suspension of 3-bromomethyl-2-bromothiophene (6.30 g), potassium acetate (9.8 g) in acetone (100 ml) was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2-bromothiophene (5.8 g). This crude product was dissolved in tetrahydrofuran (50 ml), and 1N aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-hydroxymethyl-2-bromothiophene (4.6 g). This crude product of 3-hydroxymethyl-2-bromothiophene was dissolved in methylene chloride (100 ml), manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-bromo-3-thiophenecarbaldehyde (3.92 g). The crude product of 2-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.0 g) in water (15 ml) and 30% aqueous hydrogen peroxide (2.5 ml) were added. Further, sodium chlorite (2.7 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide (2.7 g) and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-bromo-3-thiophenecarboxylic acid (2.89 g) as crystals.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH2:28]([NH:35][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Br)cc2)c2cccnc21
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NCc3ccccc3)cc2)c2cccnc21

Procedure:
3-(4-Bromo-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (111, 330.0 mg, 0.74 mmol), benzylamine (160 mg, 1.5 mmol), 2-[di(tert-butyl)phosphino]-1,1′-biphenyl (15.0 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (15.0 mg, 0.016 mmol), potassium tert-butoxide (100 mg, 0.89 mmol) and toluene (10.0 mL) were combined under an atmosphere of nitrogen. The reaction mixture was refluxed overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography to give the compound (112, 260 mg, 75%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][NH:26][CH3:27]>CN(C)C=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([N:26]([CH3:27])[CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 4.0 g (0.0112 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine in 15 ml of N,N-dimethylformamide was cooled in an ice bath and saturated with dimethylamine. After 18 hr at room temperature, 80 ml of ice water was added and the precipitate was collected by filtration and recrystallized twice from methanol to give the end product as white rods, mp 175°-179° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH:23]=O)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[Na].Cl>CO.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=Cc1cc(C=O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: C1CCNC1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: C=Cc1cc(CN2CCCC2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Eine suspension von 200 mg of the aldehyde described in Example 80.1 and 0.062 ml of pyrrolidine in 2 ml of MeOH was adjusted to pH 6 by the dropwise addition of acetic acid. Then, 46 mg of sodium cyanoborhydride were added and the mixture was stirred overnight at room temperature. It was acidified to pH 3 with 1N HCl and subsequently evaporated. The crude product was isolated by extraction and purified by chromatography on silica gel gereinigt. There were obtained 200 mg of methyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-vinyl-phenyl)-acetate as a colorless oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:13]([N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:30][N:29]=[C:28]2[C:38](OCC)=[O:39])=[C:14]2[C:19](=[CH:20][C:21]=1[Cl:22])[N:18]=[C:17]([O:23][CH3:24])[C:16]([O:25][CH3:26])=[N:15]2.[Cl-].[NH4+].O>ClCCl>[Cl:11][C:12]1[C:13]([N:27]2[C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:30][N:29]=[C:28]2[CH2:38][OH:39])=[C:14]2[C:19](=[CH:20][C:21]=1[Cl:22])[N:18]=[C:17]([O:23][CH3:24])[C:16]([O:25][CH3:26])=[N:15]2
Reactant: CCOC(=O)c1nnc(-c2ccccc2)n1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(CO)nnc3-c3ccccc3)c2nc1OC
Reaction time: 1 h
Yield: 32.4 %

Procedure:
Diisobutylaluminium hydride (1M in tetrahydrofuran, 2.5 mL, 2.5 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-(3-ethoxycarbonyl-5-phenyl-4H-1,2,4-triazol-4-yl)quinoxaline (Preparation 93, 237 mg, 0.5 mmol) in dichloromethane (10 mL) at room temperature under nitrogen. After 1 hour, a further portion of diisobutylaluminium hydride (1M in tetrahydrofuran, 1 mL, 1 mmol) was added, the mixture was stirred for a further 1 hour, then saturated aqueous ammonium chloride solution (10 mL) was added. Dichloromethane (50 mL) and water (50 mL) were added and the mixture was filtered through ARBOCEL (trade mark), washing the residue with warm dichloromethane:methanol (9:1, by volume, 100 mL). The organic layer was separated, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:ethyl acetate:methanol (1:1:0 changing to 0:1:0 changing to 0:95:5, by volume) to give the title compound (70 mg, 79%) as an off-white solid.