Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[F:66][C:67]1([F:120])[C:79]2[CH:78]=[C:77]([C:80]3[CH:81]=[CH:82][C:83]4[N:87]=[C:86]([C@@H:88]5[C@H:93]6[CH2:94][C@@H:90]([CH2:91][CH2:92]6)[N:89]5[C:95](=[O:108])[C@@H:96]([NH:103][C:104](=[O:107])[O:105][CH3:106])[CH:97]5[CH2:102][CH2:101][O:100][CH2:99][CH2:98]5)[NH:85][C:84]=4[CH:109]=3)[CH:76]=[CH:75][C:74]=2[C:73]2[C:68]1=[CH:69][C:70]([C:110]1[NH:114][C:113]([C@@H:115]3[CH2:119][CH2:118][CH2:117][NH:116]3)=[N:112][CH:111]=1)=[CH:71][CH:72]=2.Cl>>[CH3:106][O:105][C:104](=[O:107])[NH:103][C@@H:96]([CH:97]1[CH2:98][CH2:99][O:100][CH2:101][CH2:102]1)[C:95]([N:89]1[C@H:88]([C:86]2[NH:85][C:84]3[CH:109]=[C:80]([C:77]4[CH:76]=[CH:75][C:74]5[C:73]6[C:68](=[CH:69][C:70]([C:110]7[NH:114][C:113]([C@@H:115]8[CH2:119][CH2:118][CH2:117][N:116]8[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]8[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=8)=[N:112][CH:111]=7)=[CH:71][CH:72]=6)[C:67]([F:66])([F:120])[C:79]=5[CH:78]=4)[CH:81]=[CH:82][C:83]=3[N:87]=2)[C@H:93]2[CH2:94][C@H:90]1[CH2:91][CH2:92]2)=[O:108]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 939.91 [M+H]+. (102 mg, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([O:21]CC4C=CC=CC=4)=[O:20])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].CO.Cl>CN1CCCC1=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([OH:21])=[O:20])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)OCc4ccccc4)cc3c2n1
Agent: [Pd]
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2n1
Yield: 100.4 %

Procedure:
At room temperature, 1.18 g of 8-benzyloxycarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 17) is hydrogenated under a hydrogen pressure of one bar for 2 hours in a mixture of 60 ml of N-methylpyrrolidone, 20 ml of methanol, and 10 ml of 1N hydrochloric acid with 498 mg of palladium on carbon (10%). After vacuum-filtering over kieselguhr, the mixture is concentrated. The residue is extracted in a mixture of ethyl acetate, ethanol, and petroleum ether, thus obtaining 900 mg of 8-hydroxycarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester in the form of a hydrochloride.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23]Br>O>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Cc1ccc2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)cccc3Cl)c2n1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a mixture of sodium hydride (40% in oil, 24 mg) and N,N-dimethylformamide (1 ml) was added 8-hydroxy-2-methylquinoline (80 mg) in an ice-water bath. The mixture was stirred for 30 minutes at the same temperature and then 2,6-dichlorobenzyl bromide (120 mg) was added therein. The reaction mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (0.5 ml) in an ice-water bath. The precipitates were corrected by vacuum filtration and washed with water (3 ml) to give 8-(2,6-dichlorobenzyloxy)-2-methylquinoline (117 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:21][C:22]=1[CH3:23]>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20](/[CH:24]=[CH:25]/[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:21][C:22]=3[CH3:23])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1oc(/C=C/c2ccccc2)nc1CCl
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Cc1oc(/C=C/c2ccccc2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-5-methyl-2-[(E)-2-phenylethenyl]oxazole to give 4-[4-[3-(1-imidazolyl)propyl)phenoxymethyl]-5-methyl-2-[(E)-2-phenylethenyl]oxazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 94-95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)=[CH:4][CH:3]=1.CO.B(F)(F)F.[CH2:36](N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:29][CH3:36])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(O)c3ccc(F)cc3)CC[C@@H]12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-ol (225 mg, 0.57 mmol) in anhydrous dichloromethane (3 mL) is added anhydrous methanol (100 μL, 2.28 mmol), and then BF3.OEt (300 μL, 2.28 mmol, 1.0 M in THF) is added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight, and then poured into ice water. After the mixture is basified with triethylamine, the organic phase is separated and dried over MgSO4, and then evaporated to dryness under reduced pressure. The obtained residue is purified with a semi-preparative HPLC system to give 80 mg of pure product as a brown oil. 1H NMR (500 MHz, DMSO-d6) δ 7.31 (ddd, J=8.6, 5.6, 1.2 Hz, 2H), 7.18 (t, J=8.7 Hz, 2H), 6.50 (td, J=7.6, 1.3 Hz, 1H), 6.39 (d, J=7.3 Hz, 1H), 6.32 (d, J=7.9 Hz, 1H), 4.15 (td, J=6.5, 3.5 Hz, 1H), 3.49-3.37 (m, 1H), 3.31-3.22 (m, 3H), 3.15-3.04 (m, 4H), 3.02-2.91 (m, 1H), 2.77 (s, 3H), 2.70-2.61 (m, 2H), 2.29-2.11 (m, 2H), 2.09-1.97 (m, 1H), 1.92-1.81 (m, 1H), 1.78-1.63 (m, 3H), 1.60-1.49 (m, 1H), 1.49-1.37 (m, 1H), 1.37-1.22 (m, 1H). MS (ESI) m/z 410.6 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:41](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:40][CH3:41])([C:36]([F:39])([F:37])[F:38])[C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)N(CCc2ccc(Cl)c(Cl)c2)Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2[nH]ccc2c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2cc(C)cc3cc[nH]c23)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
20 mg of 5-methyl-1H-indole-7-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-amide (0.03 mmol) were dissolved in 5 ml DMF and potassium carbonate (9 mg, 0.07 mmol) and methyl iodide (3 μl, 0.05 mmol) were added. The reaction mixture was stirred over night at rt, then saturated ammonium chloride solution was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtrated and concentrated. The remaining residue was purified by silica gel filtration (hexane/EtOAc 1:1). This gave 20 mg (98%) of the title compound as a white foam. MS (ISP) 617.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:21][C:22]([NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:13]=2)[NH:6][CH:7]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)OCc1ccccc1
Temperature: 0 °C
Yield: 68 %

Procedure:
To a strirred solution of 0.83 g (4-6 mmol) of 5-fluorotryptamine and 0.48 g (0.55 mL, 5 mmol) of nmethylmorpholine in 10 mL of DMF at 0° C. was added dropwise 0.72 mL (5 mmol) of benzylchloroformate. The reaction mixture was allowed to stir at 0° C. under argon. After 1.5 hours of stirring, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting residue was purified by flash chromatography using hexane:ethyl acetate (2:1) as an eluent to yield 1 g (68%) of N-(Benzyloxycarbonyl)-5-fluorotryptamine as a white solid. mp 104°-105° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][CH:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c3) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Reactant: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(CCCCCCN(CCc2ccccc2)C(=O)C(F)(F)F)C(=O)C(F)(F)F)cc1N
Reaction time: 4 h
Yield: 55.2 %

Procedure:
N-[2-(3-Amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (2.62 g., 0.01 moles) in dry dimethylformamide (50 ml) was added dropwise with stirring to sodium hydride (0.3 g., 80% oil dispersion, 0.01 moles) in dry dimethylformamide (50 ml) under nitrogen. The solution was warmed at 60° for 30 min then cooled and N-(6-bromohexyl)-2,2,2-trifluoro-N-(2-phenylethyl)acetamide (3.80 g., 0.01 mole) was added. The solution was stirred for 4 hours then quenched with water and extracted with ethyl acetate. The extracts were washed with water dried and evaporated to give crude N-[2-(3-amino-4-methoxyphenyl)ethyl]-N'-(2-phenylethyl)-1,6-hexanediylbis (2,2,2-trifluoroacetamide) (3.1 g) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:34](=[O:35])[N:33]([CH3:36])[C:11]3[N:12]([CH3:32])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH2:20][C:21](=O)[CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:34](=[O:35])[N:33]([CH3:36])[C:11]3[N:12]([CH3:32])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:38][N:39]=[C:21]([CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4cc(COC5CCCCO5)n[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 43 above, with compound A, 1-[3-(4-bromo-phenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-(tetrahydropyran-2-yloxy)butane-1,3-dione and hydrazine monohydrate.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17](O)=O.N>>[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cnccn1
Agent: N
Product: c1cncc(-c2noc(-c3cnccn3)n2)c1

Procedure:
The titled compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and pyrazine-2-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 8.60 (dt, J=8.0, 1.9 Hz, 1 H), 8.77 (dd, J=5.0, 1.8 Hz, 1 H), 8.86-8.89 (m, 1 H), 8.89-8.91 (m, 1 H), 9.34 (dd, J=2.4, 0.8 Hz, 1H), 9.56 (d, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 226 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:11]3[N:16]=[C:15]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].Cl[C:35]([C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])=[O:36].CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:11]3[N:16]=[C:15]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([C:35](=[O:36])[C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])[CH2:22][CH2:23]4)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)sc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C(C)(C)OC(C)=O)CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-yl-2-piperidin-4-ylmethylthiazolo[5,4-d]pyrimidine (96 mg, 0.21 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (40 μL, 0.28 mmol) and NEt3 (40 μL, 0.31 mmol) in DCM (1 mL) was allowed to stir at r.t. for 30 min then concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording Acetic acid 2-{4-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-1-yl}-1,1-dimethyl-2-oxoethyl ester. LCMS (method A): RT 3.19 min [M+H]+ 592.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11](Cl)=[O:12].[Cl:14][C:15]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:16]=1[O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:28]=[C:27]([NH:29][C:11](=[O:12])[C:10]#[C:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:26]=[CH:25][C:16]=1[O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(Cl)C#Cc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.37 g (1.58 mmol) of (2,4-dichlorophenyl)propynoic acid chloride is dissolved in 15 mL of absolute toluene and while cooling with ice combined with 0.77 g (3.16 mmol) of [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine, dissolved in 10 mL of absolute toluene, and stirred for 4 hours at ambient temperature. Then the reaction mixture is extracted with ethyl acetate and dilute aqueous ammonia solution. The organic phase is extracted with water and dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol (9:1)). The product obtained is recrystallized from petroleum ether and dried in the vacuum drying chamber at 50° C. Yield: 0.21 g (30.2% of theory); melting point: 98° C.-100° C.; C21H21Cl3N2O2 (M=439.77); calc.: molecular ion peak (M+H)+: 439/441/443; found: molecular ion peak (M+H)+: 439/441/443; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[CH3:24])[C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:16]=[N:15][C:9]2[NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:8]=2[CH:7]=1.CCN(CC)CC.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:13]1[CH2:14][C:8]2[CH:7]=[C:6](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:18][C:19]3[O:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]=3[CH3:24])=[O:17])[CH:16]=[N:15][C:9]=2[NH:10][CH2:11][CH2:12]1)(=[O:38])[CH3:37]
Reactant: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCN3)oc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCNc2ncc(/C=C/C(=O)N(C)Cc3oc4ccccc4c3C)cc2C1
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A solution of (E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (105 mg, 0.280 mmol) in CH2Cl2 (6 mL) was treated with Et3N (0.05 mL, 0.36 mmol) followed by acetic anhydride (27 μL, 0.29 mmol). After stirring for 1.5 h, the mixture was diluted with CH2Cl2 (100 mL) and washed with H2O (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to a tan residue. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 96:4) gave the title compound (89 mg, 76%) as a colorless residue and as a mixture of amide rotamers: MS (ESI) m/e 419 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[NH3:12].C(O)C.O>C(O)C>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Solvent: O
Solvent: CCO
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of 2,6-dibromo-3-nitropyridine (5.00 g) in ethanol (10 ml) was added an ammonia/ethanol solution (6.8 M, 15 ml) at room temperature, and the mixture was placed in a closed reaction vessel and stirred at room temperature for 19 hr. To the reaction mixture was added water (25 ml), and the precipitate was collected by filtration. The precipitate was washed with ethanol, suspended in ethanol (55 ml), heated and cooled. The precipitate was collected by filtration to give the objective compound (3.19 g) as a yellow powder.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.[C:36]([OH:39])(=[O:38])[CH3:37].[H][H]>CO.[Pd]>[C:13]([OH:15])(=[O:14])[CH3:12].[C:36]([OH:39])(=[O:38])[CH3:37].[C:13]([OH:15])(=[O:14])[CH3:12].[NH2:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@H](CCCNC1CCN(c2ccncc2)CC1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of step (iii) (1.34 g) and acetic acid (0.48 ml) in methanol under argon was added 10% Pd on C (100 mg). The mixture was covered with a blanket of hydrogen and stirred at room temperature for 4 hr. The catalyst was then removed by filtration through a pad of kieselguhr and the pH of the filtrate was adjusted to 4 by addition of acetic acid. To this mixture, under argon, was then added a further quantity of 10% Pd on C (100 mg)., it was covered again with hydrogen and stirred at room temperature for 3 days. The catalyst was filtered off through a pad of kieselguhr and the filtrate was evaporated to dryness. Toluene (100 ml) was then added to the residue and the solvents were again removed in vacuo to give tert. butyl (S)-2-amino-5-[1-(4-pyridyl)piperidin-4-yl]aminopentanoate, triacetate salt (1.68 g) as a yellow gum: NMR (d6 -DMSO+CD3CO2D) δ1.49 (9H, s), 1.70 (6H, m), 2.23 (2H, m), 3.03 (2H, m), 3.25 (2H, m), 3.50 (1H, m), 3.96 (1H, m), 4.30 (2H, m), 7.18 (2H, d), 8.20 (2H, d); m/Z 349 (M+H)+.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([C:6]1[C:7](=[O:31])[N:8]([C:12]([NH:14][CH2:15][CH:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:30])=[C:23]([S:26](=[O:29])(=[O:28])[NH2:27])[CH:24]=3)[O:19][CH2:18][CH2:17]2)=[O:13])[CH2:9][C:10]=1[CH3:11])[CH3:5].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH2:4]([C:6]1[C:7](=[O:31])[N:8]([C:12]([NH:14][CH2:15][CH:16]2[C:25]3[C:20](=[CH:21][C:22]([O:30][CH2:1][CH3:2])=[C:23]([S:26](=[O:28])(=[O:29])[NH2:27])[CH:24]=3)[O:19][CH2:18][CH2:17]2)=[O:13])[CH2:9][C:10]=1[CH3:11])[CH3:5]
Reactant: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(O)c(S(N)(=O)=O)cc32)C1=O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Temperature: 0 °C

Procedure:
2.16 ml (0.027 mol) of ethyl iodide are added to a suspension of 9 g (0.022 mol) of 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-methyl)-6-sulfamoyl-7-hydroxychroman and 6.1 g (0.044 mol) of potassium carbonate in 60 ml of acetone. After stirring under reflux for three hours, the mixture is introduced into ice/water and cautiously acidified with concentrated hydrochloric acid. The precipitate is filtered off with suction, washed several times with cold water, dried and recrystallized from ethanol/DMF. 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-methyl)-6-sulfamoyl-7-ethoxychroman of melting point 192° C. is obtained.