Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]([C:14](=[O:37])[CH:15]([CH3:36])[CH2:16][S:17][C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:32])[C:28](=[CH2:31])[CH2:29][CH3:30])=[C:23]([Cl:33])[C:22]=1[Cl:34])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:34][C:22]1[C:23]([Cl:33])=[C:24]([C:27](=[O:32])[C:28](=[CH2:31])[CH2:29][CH3:30])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:18]([S:17][CH2:16][CH:15]([CH3:36])[C:14]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH2:7][C:6]([OH:38])=[O:5])=[O:37])=[O:35]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C2CCCC2)c(Cl)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CC)C(=O)c1ccc(OCC(=O)SCC(C)C(=O)N(CC(=O)O)C2CCCC2)c(Cl)c1Cl
Yield: 52 %

Procedure:
To a solution containing 5.2 g (8.7 mmol) of N-[3-[2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxy]acetylthio-2-methylpropanoyl]-N-cyclopentyl glycine t-butyl ester in 100 ml of methylene chloride was added 9.0 ml (117 mmol) of trifluoroacetic acid. After 12 hours the reaction mixture was carefully concentrated in vacuo and the residue was chromatographed via HPLC [methylene chloride/ether/acetic acid (88/10/2.5)]to afford 2.4 g (52%) of N-[3-[2,3-dichloro-4-(2-methylene-1-oxobutyl) phenoxy] acetylthio-2methylpropanoyl]-N-cyclopentyl glycine as a glass.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.CCN(CC)CC.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][C@@H:52]([C@@H:57]([CH3:62])/[CH:58]=[CH:59]\[CH:60]=[CH2:61])[C@@H:53]([CH3:56])[CH:54]=[O:55])=[CH:46][CH:45]=1>C(Cl)Cl>[OH:55][C@@H:54]([C@H:53]([CH3:56])[C@@H:52]([O:51][CH2:50][C:47]1[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=1)[C@@H:57]([CH3:62])/[CH:58]=[CH:59]\[CH:60]=[CH2:61])[C@@H:15]([CH3:16])[C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:17]
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)C=O
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
A solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone (2.18 g, 9.34 mmol) and methylene chloride (15 mL) is cooled to −20° C. (n-Bu)2BOTf (1.0 M in DCM, 8.7 mL, 8.7 mmol) is introduced dropwise. The reaction is allowed to warm to 0° C. NEt3 (1.15 9, 11.34 mmol) is added and the mixture is stirred at 0° C. for 1 h, then cooled to −78° C. A solution of (2R,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienal (1.95 g, 6.77 mmol) in DCM (10 mL) is added dropwise at −70° C. for 10 min. After 1 h at −74° C., the mixture is warmed to 0° C. The reaction is quenched with pH 7 buffer (15 mL). The mixture is slowly treated with a solution of 30% H2O2 in MeOH (1:2, 15 mL) at 0° C., stirred for 40 min at room temperature, and concentrated. The residue is extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with saturated aqueous NaHCO3, brine, and concentrated. Flash chromatography gives the desired compound (3.4 g, 96.4%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(N(CC)CC)C>C1COCC1>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccncn1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccncn1
Temperature: 25 °C

Procedure:
The 4-aminopyrimidine (1.0 equiv.) was dissolved in THF and acetic anhydride (5 equiv.) and triethylamine (1.5 equiv.) were added and the mixture was stirred at room temperature. The volatiles were removed in vacuo and the residue purified by preparative silica gel TLC to give the 4-acetamidopyrimidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][O:22]C(C4C=CC=CC=4)(C4C=CC(OC)=CC=4)C4C=CC(OC)=CC=4)[C@@H:17]([OH:18])[CH2:16]3)[CH:13]=[N:14][C:7]=12.[C:46](OC(=O)C)(=[O:48])[CH3:47].O>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([O:18][C:46](=[O:48])[CH3:47])[CH2:16]3)[CH:13]=[N:14][C:7]=12
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(-c5cccs5)ccnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(-c4cccs4)ccnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
Compound 7 (124 mg, 0.20 mmol) was azeotroped three times with anhydrous pyridine. This was dissolved in anhydrous pyridine (2.0 ml), and 38 μl (0.40 mmol) of acetic anhydride was further added thereto. The resulting mixture was stirred at room temperature for 2 days. The mixture was poured into water (50 ml) and extracted with methylene chloride (50 ml×3). After drying over Na2SO4, the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml anhydrous methylene chloride, and 200 μl dichloroacetic acid was added thereto at 0° C. After stirring at 2° C. for 15 minutes, the mixture was poured into 8 ml saturated aqueous sodium bicarbonate, diluted with 42 ml water, and then extracted with methylene chloride (50 ml×3). After drying over Na2SO4, the solvent was distilled off under reduced pressure. The residue was purified by flash silica gel chromatography using methylene chloride:ethyl acetate (9:1 to 3:2) as an elution solvent to give 65 mg of Compound 9 in a yield of 88%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[N:11]=[CH:10][C:9]([CH:12](OS(C)(=O)=O)[CH3:13])=[C:8]([I:19])[CH:7]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.C(Cl)(Cl)Cl>[N:1]([CH:12]([C:9]1[C:8]([I:19])=[CH:7][C:6]([F:5])=[N:11][CH:10]=1)[CH3:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)c1cnc(F)cc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(N=[N+]=[N-])c1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 42 h
Yield: 75.3 %

Procedure:
Add sodium azide (0.45 g, 7 mmol) and tetra-N-butylammonium bromide (0.12 g, 0.4 mmol) to a solution of methanesulfonic acid 1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl ester (1.2 g, 3.5 mmol) in DMF (20 mL) at 0° C. Stir the mixture at RT for 42 h. Dilute the reaction mixture with chloroform. Wash the organic phase with water and saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (20% ethyl acetate in hexane) to afford the title compound as a white solid (0.77 g, 76%). 1H NMR (400 MHz-CDCl3) δ 1.56 (d, J=6.8 Hz, 1H), 4.90 (m, 1H), 7.45 (d, J=3.2 Hz, 1H), 8.17 (s, 3H).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[CH:17]1(NC2CCCCC2)[CH2:22]CCC[CH2:18]1.C(O)C.C(I)CC.[C:37](=[S:39])=[S:38]>>[CH:11]1([NH:12][CH:13]2[CH2:5][CH2:4][CH2:3][CH2:14][CH2:1]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:18]([S:39][C:37]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:38])[CH2:17][CH3:22]
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCCI
Solvent: CCO
Product: CCCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.32 g), dicyclohexylamine (7.3 g) and 50% ethanol (55 ml) is added dropwise carbon disulfide (1.2 ml). The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise n-propyl iodide (3.4 g). The mixture is further stirred at room temperature for 10 minutes. The reaction mixture is distilled to remove the solvent. The resulting precipitates are collected by filtration and washed with ether to give dicyclohexylamine salt of the title compound. This product is treated with 10% HCl to give the title compound (4.6 g, 69%) as colorless needles, m.p. 180° C. (decomp.) (recrystallized from ethanol).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH:9]([OH:11])[CH3:10].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:11][CH:9]([CH3:10])[CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (2.86 ml, 36.9 mmol) was added dropwise to an ice-cooled solution of 1-methoxy-2-propanol (3 ml, 30.7 mmol) and triethylamine (10.27 ml, 73.7 mmol) in dichloromethane (150 ml), and the reaction stirred at room temperature for 18 hours. The mixture was washed with water, then 2M hydrochloric acid, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow oil, 5.24 g.
Reaction SMILES: [ClH:1].C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(OCC1C=CC=CC=1)=O)C.Cl.Cl.[CH2:43]([NH:45][C:46](=[O:71])[C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[C:52](=[O:70])[C@H:53]([CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:69])[NH2:68])[NH:54][C:55](=[O:62])[C@H:56]([CH2:58][CH:59]([CH3:61])[CH3:60])[NH2:57])[CH3:44].[N+](C1C=CC([O:81][C:82](=O)[C@@H:83]([CH:92]([CH3:94])[CH3:93])[NH:84][C:85]([O:87][C:88]([CH3:91])([CH3:90])[CH3:89])=[O:86])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:43]([NH:45][C:46](=[O:71])[C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[C:52](=[O:70])[C@H:53]([CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:68])[NH2:69])[NH:54][C:55](=[O:62])[C@H:56]([CH2:58][CH:59]([CH3:60])[CH3:61])[NH:57][C:82](=[O:81])[C@@H:83]([CH:92]([CH3:93])[CH3:94])[NH:84][C:85]([O:87][C:88]([CH3:89])([CH3:90])[CH3:91])=[O:86])[CH3:44]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 96 h

Procedure:
Nα -t-butoxycarbonyl-D-valyl-L-leucyl-L-arginyl-L-proline N-ethylamide hydrochloride is prepared from 3.8 g., 6.5 mmol, of Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-proline N-ethylamide hydrochloride by de-protection by the hydrogenation procedure as described in Example 2, to yield 2.9 g., 6.5 mmol, of L-leucyl-L-arginyl-L-proline N-ethylamide dihydrochloride as a glassy solid. This material is dissolved in 25 ml. of dimethylformamide and treated with 2.2 g., 6.5 mmol, of Nα -t-butoxycarbonyl-D-valine p-nitrophenyl ester. The reaction is held at room temperature for four days and is then evaporated to dryness under reduced pressure. The residue is dissolved in 10 ml. of methanol and the product precipitated by the addition of 500 ml. of anhydrous ether. The solid product is purified by chromatography over silica gel with toluene-methanol (70:30); 1.1 g.; [α]D23 -53.5° (c 1.0, methanol).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:16][C:10]1[CH:15]=[CH:14][C:13]([C:1](=[O:4])[CH:2]=[CH2:3])=[CH:12][CH:11]=1
Reactant: C=CC(=O)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc(C)cc1

Procedure:
Toluene (0.3 mL), acryloyl chloride (0.23 g), and aluminium chloride (0.33 g) were treated in the same manner as described in Example 1 to obtain the title compound (90 mg).
Reaction SMILES: [C:1]([O:12][CH2:13][CH3:14])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:21]([O:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]([O:5][CH2:8][CH:6]=[CH2:4])[C:6]=1[O:7][CH2:3][CH:2]=[CH2:1])[C:1]([O:12][CH2:13][CH3:14])=[O:11])[CH:22]=[CH2:23]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)OCC)cc(OCC=C)c1OCC=C

Procedure:
Ethyl gallate (7.92 g, commercially available, Fluka), and K2CO3 (27.6 g) in DMF (40 ml) were treated with allyl bromide (13.5 ml) as above, to give ethyl 3,4,5-triallyloxybenzoate acid (14 g): NMR (CDCl3) 1.49 (t, 3H); 4.35 (q, 2H); 4.62 (m, 6H); 5.15-5.48 (m, 6H); 6.00-6.28 (m, 3H); 7.29 (s, 1H). This crude ester was hydrolysed essentially as above to give 3,4,5-triallyloxybenzoic acid (10.4 g): NMR (CDCl3) 4.64 (m, 6H); 5.15-5.51 (m, 6H); 6.00-6.20 (m, 3H); 7.35 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C[C:18]([S:21]([CH2:24]C#N)(=[O:23])=[O:22])=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11](=[C:24]([S:8]([CH3:5])(=[O:10])=[O:9])[S:21]([CH3:18])(=[O:23])=[O:22])[C:12]#[N:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#CCS(=O)(=O)c1ccc(F)cc1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Product: CS(=O)(=O)C(=C(C#N)S(=O)(=O)c1ccc(F)cc1)S(C)(=O)=O

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(4-fluoro-benzenesulfonyl) acetonitrile is utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:44])C)=O)(C)(C)C.[Cl:45][CH2:46]Cl>Cl.C(OCC)C>[ClH:45].[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH:9]([CH3:44])[NH:8][CH:13]([CH3:46])[CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: ClCCl
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CC(C)NC(C)C4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
4-{6-[8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.250 g, 0.414 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl in diethyl ether (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the solid was dried in a vacuum oven for 24 hours at 50° C. to give 6-acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.120 g, 38.1%). 1H NMR δ(400 MHz, DMSO-d6) 9.51 (m, 2H), 9.0 (m, 1H), 8.97 (s, 1H), 8.08 (d, J=2.7 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.78 (m, 1H), 5.80 (m, 1H), 3.35 (d, J=11.5 Hz, 2H), 3.35 (m, 2H), 2.75 (dd, J=12.2, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 2.19 (m, 2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.57 (m, 2H), 1.29 (d, J=6.6 Hz, 6H). MS (APCI); M++1: Calc'd, 476.3. Found 476.1. Anal. Calc'd for C26H33N7O22.70HCl, 0.10H2O: C, 54.23, H, 6.28, N, 17.03. Found: C, 54.60; H, 6.68; N, 16.57.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=2[CH:35]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[C:31]([CH3:32])([CH3:33])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: N#CCCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccccc4OCCC#N)n3)ccc21

Procedure:
Title compound was prepared from 3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-propionitrile and 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in a manner analogous to Example 1221d. Product was isolated as an off-white foam (96 mg, 56%). 95% HPLC purity, LCMS 477.24 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.37 (d, J=8.0 Hz, 1H), 8.25 (s, 1H), 8.07-8.05 (m, 2H), 7.75 (s, 1H), 7.55 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.14-7.08 (m, 2H), 7.01 (t, J=7.7 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4.24 (t, J=7.9 Hz, 2H), 2.88 (t, J=6.2 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H), 2.12 (t, J=6.6 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=2[O:30][CH3:31])=[CH:6][CH:5]=1.[C:34](OC1C=CC=CC=1)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:1]=[N:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=2[O:30][CH3:31])=[CH:6][CH:5]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Oc1ccccc1
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C=NN)cc1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(CN=NC(C)=O)cc1
Reaction time: 3 h

Procedure:
A stirred solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (40.0 g, 87.7 mmol) in 500 mL anhydrous methylene chloride is treated with phenyl acetate (11.1 mL, 87.7 mmol). The solution is stirred 3 hours, concentrated in vacuo and the resulting liquid is purified by chromatography on silica gel (850 g) with 30% ethyl acetate/hexane as the eluent to afford 4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide as a colorless foam; CHN calculated for C28H39N3O5 :
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[NH2:15][C:16]1[C:21](=[O:22])[N:20]([CH3:23])[C:18](=[O:19])[C:17]=1[C:24]#[N:25]>>[NH2:15][C:16]1[C:21](=[O:22])[N:20]([CH3:23])[C:18](=[O:19])[C:17]=1[C:24](=[S:2])[NH2:25]
Reactant: CN1C(=O)C(N)=C(C#N)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CN1C(=O)C(N)=C(C(N)=S)C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of 100 parts of phosphorus pentasulfide and 450 parts of methylglycol is heated at the boil for 0.5 hour, after which 90 parts of 3-amino-2-cyano-N-methylmaleimide are introduced into this solution at 100° C. The mixture is stirred for 3 hours at 100° C. and then overnight at room temperature. The resulting precipitate is filtered off under suction, washed with methanol and then with water, and dried to give 65.1 parts (59% of theory) of 3-amino-2-thiocarbamyl-N-methylmaleimide.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]1([C:19]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[CH2:37][O:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:32][O:1][C:2]2[C:3]([CH3:18])=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(-c2cccc(O)c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2C)cc1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 1 g (4.1 mmol) of methyl 3′-hydroxy-2′-methylbiphenyl-4-carboxylate with 2 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 650 mg (4.7 mmol) of potassium carbonate, the desired product is obtained in the form of a colourless oil (m=2.4 9; Y=97%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([F:19])[CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:13]=[C:12]([F:11])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1cc(F)cc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,5-difluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 292-293° C.). MS(ES+) m/z 246 ([M+1]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32]C(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.IC.N1C2C(=CC=CC=2)C=C1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])[CH:16]=3)[N:11]([CH3:32])[C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[Si](Oc1ccc2[nH]c3c(c2c1)CCN(C(=O)OC(C)(C)C)C3)(C(C)C)C(C)C
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CCOCC
Solvent: CI
Product: CC(C)[Si](Oc1ccc2c(c1)c1c(n2C)CN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
A solution of 6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (175 mg, 0.39 mmol) in 3 mL of ethyl ether was added to a vigorously stirring solution of potassium tert-butoxide (263 mg) and 18-crown-6 (16 mg) in 10 mL ethyl ether. After 10 min, iodomethane (73 uL) in 0.5 mL of ethyl ether was added to the indole solution and the resulting mixture was stirred for 2 h. The solids were removed by filtration and the solvent was evaporated. Silica gel chromatography (10% ethyl acetate in hexanes) gave 9-methyl-6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (75 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1[S:12][C:13]2[CH2:19][C@@H:18]([NH:20]C(OC(C)(C)C)=O)[CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1[S:12][C:13]2[CH2:19][C@@H:18]([NH2:20])[CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)OCc3ccccc3)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCc2nc(NC(=O)OCc3ccccc3)sc2C1
Reaction time: 1 h

Procedure:
Dissolved ((S)-6-tert-butoxycarbonylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester in 20 mL of CH2Cl2. Added 20 mL of TFA. Stirred for 1 h. LC-MS analysis indicated complete deprotection of BOC group. Concentrated to give 46.0 g of ((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester trifluoroacetate as pale yellow solid.