Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(N)c2)C1
Reaction time: 1 h
Yield: 121.9 %

Procedure:
To 10% palladium-carbon (100 mg), a solution of tert-butyl 3-((3-nitrophenyl)amino)pyrrolidine-1-carboxylate (C23, 210 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 3-((3-aminophenyl)amino)pyrrolidine-1-carboxylate (C24, 231 mg).
Reaction SMILES: Cl[SiH:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[CH:10]([CH3:12])[CH3:11].[CH:13]([NH2:16])([CH3:15])[CH3:14]>CCCCCC>[CH:10]([N:3]1[CH:4]=[CH:5][N:6]([CH:7]([CH3:9])[CH3:8])[SiH:2]1[NH:16][CH:13]([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CC(C)N[SiH]1N(C(C)C)C=CN1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In an argon atmosphere, 4.24 g (20.7 mmol) of Si(iPrNCHCHNiPr)(H)Cl was dissolved in 20 mL of hexane and after adding 2.51 g (42.4 mmol) of isopropylamine, the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 75° C./3.7×102 Pa) to obtain 1,3-diisopropyl-2-isopropylamino-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)NHiPr) as a colorless liquid (yielded amount: 4.10 g, yield: 87%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:40]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CS(=O)(=O)CCOC(=O)Cl
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccn1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethylamide hydrochloride and 2-(methylsulfonyl)ethyl chloroformate. Yield: 72% of theory, C30H33N7O7S (635.7); Rf value: 0.23 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=636; (M+H+Na)++=329.8.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A 100 mL round-bottom flask, was charged with 4-bromo-2-phenoxybenzaldehyde (1.00 g, 3.61 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.674 g, 3.62 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.30 g, 10.8 mmol, 3.01 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with H2O (10 mL). The resulting mixture was extracted with dichloromethane (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92) to provide 1.20 g (74% yield) of tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 447 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][C:24]3[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=3)[C:9]2=[O:31])=[CH:4][CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=3)[CH2:11][N:10]([CH2:23][C:24]3[CH:25]=[N:26][C:27]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:29]=3)[C:9]2=[O:31])=[CH:6][CH:7]=1
Reactant: O=C1N(Cc2ccc(Cl)nc2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Reactant: C1CCNCC1
Solvent: c1ccncc1
Product: O=C1N(Cc2ccc(N3CCCCC3)nc2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
A mixture of (S)-3-(4-chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (34 mg, 0.073 mmol), piperidine (0.5 mL) and pyridine (2 mL) are heated for 2 days at 130° C. The residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 6.4 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.50-7.41 (m, 4H), 7.32-7.27 (m, 3H), 7.15 (d, J=9.2 Hz, 2H), 5.45 (dd, J=9.2, 6.4 Hz, 1H), 4.34 (s, 2H), 3.88 (t, J=9.2 Hz, 1H), 3.60-3.58 (m, 4H), 3.16 (dd, J=9.0, 6.2 Hz, 1H), 1.72-1.61 (m, 6H); HPLC-MS calculated for C27H26ClF3N4O (M+H+) 515.1, found 515.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(-c2ccncc2)nn1
Reaction time: 0.08 h

Procedure:
Ethyl 3-(pyridin-4-yl)-1,2,4-triazin-6-carboxylate (200 mg) was dissolved in a mixed solvent of tetrahydrofuran (5 ml) and methanol (5 ml) at room temperature. A 1N aqueous solution (1.00 ml) of sodium hydroxide was added to the reaction mixture in one portion. After stirring for 5 minutes, the reaction mixture was distilled under reduced pressure to remove tetrahydrofuran and methanol, followed by neutralization with 1N hydrochloric acid. The reaction mixture was concentrated to dryness, whereby 3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic acid was obtained as a crudely purified product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:23]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(CCCO)cc1
Reactant: CCc1nc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(Nc2ccc(CCCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 75 °C
Yield: 35.4 %

Procedure:
2-Chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.150 g, 0.59 mmol) and 3-(4-aminophenyl)propan-1-ol (0.130 g, 0.89 mmol) were suspended in acetic acid (5 mL). The mixture was heated to 75° C. for 2 h. After this time, the reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.077 g, 35%) as a yellow solid. MW=368.86. 1H NMR (DMSO-d6, 500 MHz) δ 10.19 (s, 1H), 8.41-8.31 (m, 2H), 7.71-7.67 (m, 3H), 7.60 (t, J=8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.45 (t, J=5.5 Hz, 1H), 3.43 (q, J=5.5 Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.51-2.49 (m, 2H), 1.75-1.69 (m, 2H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH2:3][S:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][N:8]=1.[CH3:13][NH2:14]>C(O)C>[CH3:13][N:14]=[C:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4][CH2:3]1
Reactant: CN
Reactant: ClC1=NCc2ccccc2SC1
Solvent: CCO
Product: CN=C1CSc2ccccc2CN1

Procedure:
3-Chloro-2,5-dihydro-1,4-benzothiazepine (5 g) and a 33% solution of methylamine in absolute ethanol (150 ml) were heated under reflux for one hour. The mixture was cooled and filtered. Purification of the residue by flash chromatography using ethyl acetate/ethanol (1:1) as eluent gave 3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethanol. Yield 0.51 g (m.p. 278°-280° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[CH3:40][N:41]([CH3:50])[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18]([N:47]2[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][N:41]([CH3:50])[CH3:40])[CH2:45][CH2:46]2)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: CN(C)CCN1CCNCC1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CCN(CCN(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-({4-[2-(dimethylamino)ethyl]piperazin-1yl}sulfonyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (COMPOUND CCC8) and N,N-dimethyl-2-piperazin-1-ylethanamine by a procedure analogous to that described in EXAMPLE CCC25, STEP B. Mass spectrum (ESI) 742 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6].C[Si]([C:32]#[CH:33])(C)C.CCN(CC)CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6])#[CH:33]
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1cc(C(=O)Nc2cc(-n3cnc(C)c3)cc(C(F)(F)F)c2)ccc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In a pressure tube with one end sealed, add 485 mg 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (1.0 mmol) from Step 2, 500 mg trimethylsilylacetylene (5.0 mmol), 19 mg Cu I (0.1 mmol), 7 mg Pd(PPh3)2Cl2 (0.01 mmol), 1.0 mL Et3N in 3.0 mL acetonitrile, and after Nitrogen replacement, the mixture is stirred at 80° C. for 2 h. After cooling to room temperature, the solution was filtered by 2 cm silica gel column. The filtration is washed three times with ethyl acetate and is concentrated to brown solid which is further dissolved in 5 mL methanol. The solution is then added with 980 mg K2CO3 and stirred at room temperature for 3 h. The solid was filtered off and the solution was concentrated to column chromatography f 344 mg desired product. (90%)
Reaction SMILES: [CH2:1]([C:3]([OH:24])([CH2:22][CH3:23])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15]C(=O)C(F)(F)F)[CH:9]=[CH:10][CH:11]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[NH2:15][CH2:14][CH2:13][CH2:12][C:8]1[CH:7]=[C:6]([C:5]#[C:4][C:3]([CH2:22][CH3:23])([OH:24])[CH2:1][CH3:2])[CH:11]=[CH:10][CH:9]=1
Reactant: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(O)(C#Cc1cccc(CCCN)c1)CC
Temperature: 45 °C
Reaction time: 4 h

Procedure:
N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (12) (0.660 g, 1.93 mmol) was dissolved in MeOH (15 mL), and an aqueous solution of K2CO3 (0.42 g/3 mL) was added. The resulting mixture was stirred at 45° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure then partitioned between EtOAc (50 mL) and water (50 mL). The combined organics were dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (80 to 100% (9:1 EtOAc: 7M NH3 in MeOH): hexanes gradient) gave 1-(3-(3-aminopropyl)phenyl)-3-ethylpent-1-yn-3-ol (13) as a light yellow oil. Yield (0.421 g, 89%): 1H NMR (400 MHz, DMSO-d6) δ 7.15-7.26 (m, 4H), 5.11 (s, 1H), 2.56 (t, J=7.6 Hz, 2H), 2.47 (t, J=5.2 Hz, 2H), 1.55-1.65 (m, 6H), 1.39 (br s, 2H), 0.97 (t, J=7.6 Hz, 6H).
Reaction SMILES: [OH-].[K+].COC(=O)[C:6]([C:16](=[O:18])[CH3:17])([CH2:13][CH2:14][CH3:15])[CH:7]([CH3:12])[C:8]([O:10]C)=[O:9]>CO.O>[C:16]([CH:6]([CH2:13][CH2:14][CH3:15])[CH:7]([CH3:12])[C:8]([OH:10])=[O:9])(=[O:18])[CH3:17]
Reactant: CCCC(C(C)=O)(C(=O)OC)C(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(C(C)=O)C(C)C(=O)O
Temperature: 105 °C

Procedure:
KOH (6.9 g, 123 mmol) is added to a solution of 2-acetyl-3-methyl-2-propyl-succinic acid dimethyl ester (5.0 g, 20.5 mmol) in MeOH (25 ml) and water (25 ml). The mixture is refluxed overnight and excess MeOH is evaporated. The residue is acidified by concentrated HCl to pH=2 and is refluxed (oil bath 105° C.) overnight. The mixture is extracted with EtOAc (4×75 ml) and the combined extracts are extracted with 2N aqueous NaOH (4×50 ml). The NaOH solution is then cooled to 0° C. and acidified with concentrated HCl. The mixture is extracted with EtOAc (4×75 ml) and the combined extracts are washed with brine (100 ml), dried (Na2SO4) and evaporated in vacuo, providing 3-acetyl-2-methyl-hexanoic acid as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (362 mg, 1.2 mmol) and 3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H8) (300 mg, 1.0 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (312 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[OH:16][CH2:17][C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:19][CH2:18][C:17]([NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=[O:16]
Reactant: O=C(O)CO
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)CO)C1

Procedure:
A mixture of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.0 equiv.), 2-hydroxyacetic acid (1.80 equiv.), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.0 equiv.), and N,N-dimethylpyridin-4-amine (0.20 equiv.) was stirred in DCM (0.1 M) at room temperature overnight. The reaction was quenched with water and washed (3×) with water. The combined aqueous fractions were then back-extracted with chloroform (4×) and the combined organics were dried over Na2SO4, filtered, and concentrated. The resulting oil was passed through a pad of SiO2 gel using 5-50% MeOH/DCM and concentrated to yield (R)-tert-butyl 2-((2-hydroxyacetamido)methyl)morpholine-4-carboxylate as an oil. LCMS (m/z) (M+H)=175.1 (-Boc), Rt=0.55 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][NH:19]C(OCC=C)=O)=[CH:14][CH:15]=2)[C:10]([C:26](=[NH:35])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCOCC1>C(Cl)Cl.[Pd].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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][NH2:19])=[CH:14][CH:15]=2)[C:10]([C:26](=[NH:35])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)NCCc1ccc2c(c1)c(C(=N)NC(=O)OC(C)(C)C)cn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)NC(=N)c1cn(C(=O)OC(C)(C)C)c2ccc(CCN)cc12
Reaction time: 0.75 h

Procedure:
A solution of 1-tert-Butoxycarbonyl-3-(tert-butoxycarbonylcarbamimidoyl)-5-(2-[allyloxycarbonylamino]ethyl)indole (reference example 8) (0.199 g, 0.409 mmol), 50 mg tetrakis(triphenylphosphine)palladium (0), and 0.078 mL (0.90 mmol) morpholine in 20 mL CH2Cl2 is stirred for one hour. TLC showed some starting material present, so another 50 mg palladium catalyst is added. After stirring 45 minutes, the reaction mixture is concentrated, and the residue chromatographed (10:1 CH2Cl2:7N NH3 in MeOH) to provide the product as a yelow solid. 1H NMR (CDCl3): δ 1.57 (9H, s), 1.64 (9H, s), 2.88 (4H, m), 7.23 (1H, dd, J1=8.7 Hz, J2=1.2 Hz), 7.77 (1H, s), 8.16 (1H, d, J=8.7 Hz), 8.25 (1H, s). MS (EI) m/z 402 M+.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Si](C)(C)C)[CH:4]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(OC(=O)C)(=O)C>[N+:15]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:14])([CH3:13])[CH3:1])[CH:4]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: C[Si](C)(C)c1cccc([Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)c1cccc([N+](=O)[O-])c1
Yield: 36 %

Procedure:
To a solution of 1.50 g (6.75 mmol) of m-bis(trimethylsilyl)benzene in 4.0 ml of acetic anhydride was added dropwise a solution of 1.6 ml (35.6 mmol) of 94% nitric acid in 5 ml of acetic anhydride at 130° C. with stirring. The mixture was stirred for 30 minutes. The reaction mixture was poured into a mixture of ice and 2% potassium carbonate solution and methylene chloride and separated. The aqueaus layer was extracted with methylene chloride. The organic layer was washed successively with water and 2% potassium hydroxide solution, dried and evaporated. The residue was purified by column chromatography on silica gel [eluent: methylene chloride-cyclohexane (1:3-1:5)] to give 475 mg of pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH3:24])=[O:34]
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline 50 mg) was dissolved in chloroform (5 ml), and 2-methoxyphenyl isocyanate (24 μl) was then added to the solution. The mixture was stirred at 60° C. for one hr. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 39 mg (yield 54%) of the title compound.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([S:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1)#[N:3].C([OH:30])(C)(C)C.[OH-].[K+]>O>[ClH:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([S:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=1)(=[O:30])[NH2:3]
Reactant: CN(C)CCSc1nc2ccccc2cc1-c1ccc(C#N)cc1
Reactant: CC(C)(C)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCSc1nc2ccccc2cc1-c1ccc(C(N)=O)cc1

Procedure:
A mixture of 3-(p-cyanophenyl)-2-(2-dimethylaminoethylthio)quinoline hydrochloride (see Ex. 30, 0.65 g.), t-butanol (25 ml.) and potassium hydroxide (0.6 g.) was heated at 40° for 1 hr. Water (20 ml.) was added to the mixture and the t-butanol was evaporated. Additional water (20 ml.) was added, and the mixture was extracted with chloroform (3×30 ml.). The chloroform extract was washed with water (2×10 ml.) and dried (MgSO4). The solvent was evaporated and the residue was crystallised from ethanol. The crystalline material was dissolved in ethanol (50 ml.) and ethereal hydrogen chloride was added to the solution. The solvents were evaporated and the residue was crystallised from ethanol-diethyl ether to give 3-(p-carbamoylphenyl)-2-(2-dimethylaminoethylthio)quinoline hydrochloride, m.p. 253°-5°.