Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:37](OCC)=[O:38]>>[CH:37]([N:28]1[CH2:29][C@H:25]([NH:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]([CH3:2])[CH:12]=3)=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C@H:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)=[O:38]
Reactant: CCOC=O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Yield: 61 %

Procedure:
According to the procedure of Example 17, Step 3, the reaction of 320.4 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride with ethyl formate provided 191 mg (61% yield) of tert-butyl cis-1-formyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate. MS: 526.2(M+H)+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25]([O:33][CH:34](Cl)[CH3:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][CH2:35][CH2:34][O:33][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13])(=[O:7])=[O:6]
Reactant: CC(Cl)OC(=O)c1ccccc1
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OCCOC(=O)c1ccccc1
Yield: 110 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (0.4 g, 0.99 mmol) dissolved in 5 mL of anhydrous toluene was reacted with 0.55 g (3.0 mmol) of 1-chloroethyl benzoate (23) in the presence of 0.33 g (1.1 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.6 g of a mixture of the title compound (38a) and (3R)-4,4-dimethyl-3-(1,1,2,2-tetramethyl-1-silapropoxy)-3,4,5-trihydrofuran-2-one (4a). MS (ESI) m/z 573.01 (M+Na)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH3:7][C:8]([CH3:10])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH3:7][C:8]1([CH3:10])[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1
Reactant: CC(C)=O
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CC1CCSC(C)(C)O1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 3.2 grams (0.055 moles) of acetone is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of about 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 7.2 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4](C)[C:5]([O:7][CH3:8])=[O:6].N[C@@H:11](C)CC(O)=O>>[ClH:1].[NH2:2][C@@H:3]([CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: C[C@H](N)CC(=O)O
Reactant: COC(=O)C(C)CN
Agent: Cl
Product: COC(=O)C[C@H](C)N

Procedure:
Compound 58-B was prepared in analogy to compound W in Example 20 by using (S)-3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH2:12].[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].CCN(C(C)C)C(C)C.O>C1COCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:12][C@@H:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:11][C@@H:3]2[O:2][CH3:1])[N:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
To a solution of (1R,2S)-2-methoxyindan-1-amine (242.8 mg, 0.001488 mol) in THF (1 mL) was added cyanuric chloride (313 mg, 0.00170 mol) at 0° C., followed by DIPEA (300 μL, 0.002 mol) and the reaction was stirred at 0° C. for 1.5 hours. The reaction was poured into water and extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to obtain 229.1 mg (49%) of the title compound. LC/MS: Rt=2.03 min, ES+ 311 (FA standard).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:25](OCC(Cl)=O)(=[O:27])[CH3:26].[OH-].[Na+].Cl>COCCOC.CO>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:26]2[CH2:25][OH:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: Cc1c(Cl)cccc1Cn1c(CO)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (1 g, 2.73 mmol) in 1,2-Dimethoxyethane (DME) (20 ml) at 0° C. was added acetoxyacetyl chloride (0.586 ml, 5.45 mmol). The mixture was stirred at room temperature for 2 h, then stirred at 50° C. overnight. The mixture was quenched with methanol and concentrated. To the resulting residue in Methanol (12 ml) was added 6N NaOH (0.9 mL, 5.45 mmol). The mixture was stirred at room temperature for 60 min, then acidified (˜pH 5) with 1N HCl. The solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated. Reversed-phase HPLC purification provided 4-[(3-chloro-2-methylphenyl)methyl]-5-(hydroxymethyl)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (250 mg, 22%); LC/MS: MS (ES+) m/e 407 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 3.51 (m, 4H), 3.67 (m, 4H), 4.32 (d, J=5.6 Hz, 2H), 5.57 (s, 2H), 5.64 (t, J=5.6 Hz, 1H, OH), 6.51 (d, J=7.6 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=7.8 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH2:6][NH2:7].CO.Cl>O>[NH:2]=[C:3]([NH:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:8]([OH:10])=[O:9])[NH2:2])[CH2:4][CH:5]=[CH2:6]
Reactant: NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CO
Solvent: O
Product: C=CCC(=N)NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
L-Ornithine HCl (1.68 g, 10 mmol) and cupric acetate (0.5 g, 10 mmol) were dissolved in water (20 ml) and stirred for 10 minutes at room temperature. The solution was then filtered to remove minor impurities and cooled to 0° C., and the pH was adjusted to 9.5 by addition of cold 10% NaOH. 3-Butenyl imidate (15 mmol), prepared separately from the corresponding nitrile, methanol and gaseous HCl by the method described in Scannell, J. P., J. Antibiot. 25, 179-184 (1972) was then added, and the mixture was allowed to stir at pH 9.0-9.5 for 1 hour at 0° C. and for 2 hours at room temperature. The pH was then adjusted to 7.4 with cold dilute HCl, and the mixture was stirred at room temperature overnight. Hydrogen sulfide gas was bubbled through the solution, and the resulting copper sulfide precipitate was removed by filtration through charcoal. The filtrate was passed through Chelex to remove any residual Cu2+, and the clear solution was evaporated to dryness by rotary evaporation under reduced pressure. The residue was washed with ethyl acetate, and the product was crystallized from ethanol to give pure N5 -(1-imino-3-butenyl)-L-ornithine, which may be referred to as L-VNIO--m.p. 162° C. (dec); H NMR(D2O) ; δ1.65-2.1 (m, 4H), 3.3 (d, 2H), 3.4 (t, 2H), 3.8 (t, 1H), 5.4 (m, 2H), and 5.95 (m, 1H); 13C NMR (D2O): δ25.43, 30.35, 39.37, 44.28, 56.93, 124.16, 131.55, 168.72, and 176.98; FABMS (fast atom bombardment mass spectrometry): m/e 200 (M+H). Examples below establish L-VNIO as the first neuronal isoform selective, mechanism-based amino acid inactivator of NOS.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[NH:1]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-aminoindan-1-one (7.2 g, 11.8 mmol) in conc. HCl (20 mL) at 0° C. was added dropwise an aqueous solution of NaNO2 (0.9 g, 13 mmol). After 30 min, a solution of SnCl2.2H2O (5.9 g, 26.2 mmol) in conc. HCl was added dropwise at such a rate that the reaction temperature never rose above 5° C. After the addition was completed, the mixture was stirred at RT for 2 h. The mixture was extracted with Et2O to afford 6-hydrazinoindan-1-one. MS (ESI) m/z: 199 (M+H+).
Reaction SMILES: NN.[CH2:3]([O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][C:42](=[CH2:44])[CH2:41][CH:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[N+:47]([O-])=O)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C:20](=[CH2:22])[CH2:19][CH:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[N+:25]([O-])=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[CH2:5]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][CH:20]([CH3:22])[CH2:19][CH:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[NH2:25])[CH2:4][CH2:3][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][CH:42]([CH3:44])[CH2:41][CH:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[NH2:47]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: [Ni]
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(OCCCOc2cc(OC)c(C(=O)N3CC(C)CC3CO)cc2N)c(N)cc1C(=O)N1CC(C)CC1CO
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) was added dropwise to a solution of the diol 35 (95 mg, 0.145 mmol) and Raney Ni (20 mg) in MeOH (15 mL) heated at reflux. After 1 hour at reflux TLC (90% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (20 mg) and hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed complete reaction. The reaction mixture was then treated with enough Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 hours. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl2 (30 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the bis-amine (36) as a yellow oil (54 mg, 63%): 1H NMR (270 MHz, CDCl3) (diastereoisomers) δ 6.73 (s, 2Harom), 6.32 (s, 2Harom), 4.60-4.30 (m, 2H, NCHCH2OH), 4.19 (t, 4H, J=5.87 Hz, OCH2CH2CH2O), 3.78-3.50 (m, 14H, NCHCH2OH, NCH2CHCH3 and OCH3), 2.40-1.55 (m, 8H, NCH2CHCH3, OCH2CH2CH2O and NCH2CHCH3CH2), 1.00-0.95 (m, 6H, NCH2CHCH3); MS (EI), m/z (relative intensity) 600 (M+, 16), 459 (46), 345 (16), 206 (13), 186 (17), 180 (31), 166 (37), 149 (6), 142 (76), 100 (6), 98 (13), 97 (29), 84 (81), 69 (7), 55 (100).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].F[C:21]1[C:26]([F:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(Cl)Cl>[C:16]([C:3]1[C:2](=[O:1])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:21]3[C:26]([F:27])=[CH:25][C:24]([C:28]([F:31])([F:29])[F:30])=[CH:23][N:22]=3)=[CH:10][CH:9]=2)[CH2:5][C:4]=1[OH:15])(=[O:19])[CH2:17][CH3:18]
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: CCC(=O)C1=C(O)CC(c2ccc(S)cc2)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(c2ccc(Sc3ncc(C(F)(F)F)cc3F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 4.0 g (0.0145 mol) of 3-hydroxy-5-(4-mercaptophenyl)-2-propionyl-cyclohex-2-en-1-one in 50 mL of acetonitrile was added 3.90 g (0.0212 mol) of 2,3-difluoro-5-(trifluoromethyl)pyridine and 4.50 g (0.0326 mol) of powdered potassium carbonate. The mixture was stirred one hour at ambient temperature and then heated at reflux for 1.5 hours and cooled to room temperature. The reaction mixture was diluted with 150 mL of water and 150 mL of methylene chloride. The organic layer was separated, washed twice with 150 mL portions of water and dried over Na2SO4. The solvent was removed in vacuo leaving 5.7 g of the crude product which was purified by column chromatography using methylene chloride as the eluent. Recrystallization of the crude from ethanol gave the above named product in a yield of 2.25 g (35 percent of theoretical). The product melted at 152°-154° C.; 1H NMR (CDCl3): δ 1.10 (t, 3H, CH3CH2 --), 2.55-3.65 (m, 7H, ring protons and CH3CH2 --), 7.15-8.50 (m, 6H, ArH), 18.2 (s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:28]([NH2:30])=[O:29])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH:31]([S:33]([CH:36]=[CH2:37])(=[O:35])=[O:34])=[CH2:32]>CC(O)C>[O:34]=[S:33]1(=[O:35])[CH2:36][CH2:37][N:1]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][O:25][CH2:26][CH2:27]6)=[CH:19][CH:20]=5)[CH:12]=[C:11]([C:28]([NH2:30])=[O:29])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:32][CH2:31]1
Reactant: C=CS(=O)(=O)C=C
Reactant: NC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1[nH]c1cc(N)ccc12
Solvent: CC(C)O
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A mixture of 7-amino-2-(4-(morpholinomethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (50 mg, 0.125 mmol), vinyl sulfone (0.13 mL, 1 3 mmol) in 2-propanol (3 mL) was stirred at 100° C. overnight. The solvent was removed and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-(1,1-dioxido-4-thiomorpholinyl)-2-(4-(4-morpholinylmethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (6 mg, 10.97 μmol, 8.81% yield). MS (ESI) m/z 520.22 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.22 (1H, s), 8.54 (1H, br. s.), 8.30 (1H, s), 8.22 (2H, d, J=8.24 Hz), 8.09 (1H, d, J=8.55 Hz), 7.82 (1H,s),7.46 (2H, d, J=7.93 Hz), 7.32 (1H, d, J=2.14 Hz), 7.07 (1H, dd, J=8.85, 2.14 Hz), 3.88 (4H, br. s.), 3.58-3.65 (4H, m), 3.55 (2H, s), 3.20-3.27 (4H, m), 2.41 (4H, br. s.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[CH3:54][C:55]1([CH3:62])[CH2:60][CH2:59][CH2:58][CH:57]([NH2:61])[CH2:56]1>C1COCC1>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:61][CH:57]3[CH2:58][CH2:59][CH2:60][C:55]([CH3:62])([CH3:54])[CH2:56]3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)CCCC(N)C1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)CCCC(NC(=O)c2cc3nc(Nc4c(Cl)cncc4Cl)[nH]c3c3c2OC(C)(C)C3)C1
Yield: 11.2 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.070 g, 0.178 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.114 g, 0.355 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 3,3-dimethylcyclohexanamine (0.100 g, 0.787 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 0.93 (s, 6H), 1.07-1.11 (m, 2H), 1.23-1.29 (m, 2H), 1.33 (s, 6H), 1.49-1.54 (m, 2H), 1.80 (s, 2H), 3.00 (s, 2H), 3.80 (m, 1H), 7.20 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 8.43 (s, 2H), 10.89 (s, 1H), 11.41 (s, 1H); MS [M+H]+: 502.31.
Reaction SMILES: C([O:8][C:9](=[O:35])[C@H:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:11][C:12]([N:14]([CH2:16][CH2:17][N:18]([C:20]([N:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1)=[O:21])[CH3:19])[CH3:15])=[O:13])C1C=CC=CC=1>CO.[OH-].[Na+]>[S:25]1[CH2:26][CH2:27][N:22]([C:20]([N:18]([CH2:17][CH2:16][N:14]([CH3:15])[C:12]([NH:11][C@H:10]([C:9]([OH:35])=[O:8])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:13])[CH3:19])=[O:21])[CH2:23][CH2:24]1
Reactant: CN(CCN(C)C(=O)N1CCSCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCN(C)C(=O)N1CCSCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of N-[N-[2-(N-thiomorpholinocarbonyl-N-methylamino)ethyl]-N-methylaminocarbonyl]-L-phenylalanine benzyl ester (1.50 g) in methanol (30 ml) was added in 1N sodium hydroxide aqueous solution (6 ml) at ambient temperature. After being stirred for 3 hours at the same temperature, the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with 5% hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give N-[N-[2-(N-thiomorpholinocarbonyl-N-methylamino)ethyl]-N-methylaminocarbonyl]-L-phenylalanine (1.14 g) as an oil. Rf : 0.31 ( chloroform:methanol:acetic acid, 16:1:1, V/V)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]2[C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)=[N:17][CH2:18][CH2:19][C:7]=12)[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]2[C:16]([C:20]3[CH:21]=[CH:22][C:23]([S:26][CH3:27])=[CH:24][CH:25]=3)=[N:17][CH:18]=[CH:19][C:7]=12)[CH3:2]
Reactant: CCOC(=O)Cc1c2n(c3ccc(F)cc13)C(c1ccc(SC)cc1)=NCC2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)Cc1c2cc(F)ccc2n2c(-c3ccc(SC)cc3)nccc12
Reaction time: 2 h

Procedure:
2 g of 7-fluoro-1-(p-methylthio-phenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl ester are heated under reflux, while stirring, in 20 ml of diphenyl ether with 0.5 g of palladium-on-carbon (10%). After 2 hours, a further 0.5 g of palladium-on-carbon is added and the mixture is heated for a further 3 hours. After filtering off the catalyst, the reaction mixture is concentrated in vacuo, the residue is taken up in a little ethyl acetate and chromatographed over silica gel. Using hexane/ethyl acetate (9:1) fractions are obtained which, after concentration by evaporation and recrystallization from ether, yield 7-fluoro-1-(p-methylthio-phenyl)pyrimido[1,6-a]indole-5-acetic acid ethyl ester having a melting point of 120°-122°. ##STR31## The following are obtained in an analogous manner:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:7]([C:6]4[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=4[O:4][C:1](=[O:3])[CH3:2])=[O:8])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CC(=O)Oc1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 3, making variations only as required to use acetylsalicyloyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (39% yield). 1H NMR (500 MHz, CDCl3) δ 8.06, 8.00, 7.00, 7.47, 7.34-7.29, 7.18, 6.98, 4.00-3.72, 3.60-3.48, 2.28, 1.52, 0.76, 0.48, 0.10. MS (ES+) m/z 438 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>>[C:23]([NH:22][CH2:21][CH2:20][NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])(=[O:25])[CH3:24]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-(2-Acetylamino-ethyl)-3-(2-chloro-4-iodo-phenylamino) -isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.44 mmol N-(2-amino-ethyl)-acetamide LC/MS [8.38 min; 4.59 (M+1)]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:14][C:15]1[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].O>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][O:27][C:25]([C:17]1[CH:16]=[C:15]([NH:14][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:24]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=1)=[O:26]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(=O)OC)c1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
A solution of 4-nitrophenylisocyanate (2.17 g, 12.83 mmol) in anhydrous DCM (15 ml) was added dropwise to a stirred suspension of dimethyl 5-aminoisophthalate (7.23) (2.71 g, 12.83 mmol) in DCM (35 ml). The reaction mixture was stirred for 1 h under an inert atmosphere after which it was diluted with ethyl acetate (100 ml) to dissolve a yellow precipitate which had formed during the reaction. This gave a yellow solution which formed a white precipitate on addition of water (30 ml). The precipitate was collected by filtration, repeatedly washed with water, and dried under reduced pressure. This gave a white solid which was recrystallised from acetone/petrol 40-60 to give the title compound 7.67 as a white powder (2.53 g, 53%). M.p. 193°-195° C.; m/z (+EI) 748 (5%, 2M+H+), 374 (100%, M+H+), 373 (32%, M), 342 (35%, M+H+-OMe); δH (250 MHz, d6 -DMSO) 3.85 (s, 6H, 2×OCH3), 7.70 (2H, d, J 7.5 Hz, 2×Ar--H), 8.10 (1H, s, Ar--H), 8.25 (2H, d, J 7.5 Hz, 2×Ar--H) 8.40 (2H, s, Ar--H), 9.50 (1H, s, NH), 9.55 (1H, s, NH); δC (62.5 MHz, CD3OD) 52.96. 118.28, 123.40, 123.65, 131.13, 140.65, 141.73, 146.43, 152.41, 165.74; RF 0.19 [DCM/methanol (95:5)].