Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[OH:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N:5]1[CH:6]=[CH:7][CH:2]=[C:3]([CH2:8][O:9][C:17]2[C:12]([CH:11]=[O:10])=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: O=Cc1cnccc1Cl
Reactant: OCc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=Cc1cnccc1OCc1cccnc1

Procedure:
4-chloro-3-pyridine aldehyde (1.0 g, 7 mmol, 1.0 eq), 3-hydroxymethylpyridine (5.4 g, 49.45 mmol, 7 eq) and p-toluenesulfonic acid mon hydrate (1.3 g, 7.0 mmol, 1.0 eq) in benzene (30 mL) were heated using a Dean-Stark trap for 24 h. Solvent was removed and purified by column chromatography to provide the alkylation product. MS: exact mass calculated for C12H1N2O2, 214.22; m/z found, 215 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCCN1c1ccc(N)cc1
Yield: 72.2 %

Procedure:
A solution of 1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.55 g, 2.2 mmol) in methanol (15 ml) was hydrogenated over 10% Pd—C (50 mg) at 30 psi until no further gas uptake was observed. The reaction mixture was then filtered over celite and the filtrate evaporated to yield 1-(4-amino-phenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.35 g, 72%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[NH:13][CH:14]=[C:15]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16](=[O:18])[N:17]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:2]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]3[NH:13][CH:14]=[C:15]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[C:16](=[O:18])[N:17]=3)=[CH:6][C:3]=2[C:4]#[N:5])=[CH:31][C:30]=1[C:36]([F:37])([F:38])[F:39]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(C#N)c3)nc2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.3 %

Procedure:
To a solution of 2-fluoro-5-[2-(5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4-oxo-1,4-dihydro-2-pyrimidinyl)ethyl]benzonitrile (80 mg, 0.219 mmol) and 4-chloro-3-(trifluoromethyl)phenol (64.6 mg, 0.328 mmol) in NMP (2 mL), K2CO3 (60.5 mg, 0.438 mmol) was added. The reaction vessel was sealed and stirred at room temp for 10 min, and heated by microwave to 150° C. for 2 h. Purification via MDAP then afforded the title compound as a white solid (30 mg, 25.3% yield). LCMS: rt=3.19 min, [M+H+]=542
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:8][CH:9]=1)=[O:4].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:6]2[CH:7]=[CH:8][CH:9]=[C:5]2[C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[C:12]([F:18])[CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCl)c1cccn1Cc1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CN1CCN(c2ccccc2)CC1)c1cccn1Cc1ccc(Cl)cc1F

Procedure:
A mixture of 2-chloroacetyl-1-(4-chloro-2-fluorobenzyl)pyrrole, N-phenylpiperazine and triethylamine in methanol is treated by the procedure described in Example 1b to produce 1-(4-chloro-2-fluorobenzyl)-2-[α-(4-phenylpiperazino)acetyl]pyrrole.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]([N:31](C)[C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]=1[CH3:47])(OC(C)(C)C)=O>>[Cl:21][C:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:35]5[CH:36]=[N:37][C:32]([NH:31][CH3:24])=[C:33]([CH3:47])[CH:34]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[CH:19][N:18]([CH3:20])[N:17]=1
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N(C)C(=O)OC(C)(C)C
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 6-(N-boc-methylamino)-5-methylpyridine-3-boronic acid pinacol ester (Combi-Blocks, San Diego, USA, 58.8 mg, 0.176 mmol) to give crude boc-protected title compound that was treated for 30 min at rt with trifluoroacetic acid (0.5 ml) and then purified by prep. HPLC to give the title compound as an off-white foam. (HPLC: tR 2.24 min (Method A); M+H=434 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.40 (s, 1H), 8.14-8.12 (m, 1H), 8.05-8.03 (m, 1H), 7.90-7.85 (m, 1H), 7.38-7.37 (m, 2H), 6.28-6.20 (br, 1H), 4.01 (s, 3H), 3.58 (s, 3H), 2.88 (m, 3H), 2.11 (s, 3H))
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)=[O:21])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)=[O:21])=[CH:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(Br)ccc12
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc2c(C)noc2c1
Yield: 52.9 %

Procedure:
Example 6 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 17, 16 mg) to give the title compound as an oil (8.6 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.O.[NH2:33][NH2:34]>>[NH:33]([C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1)[NH2:34]
Reactant: NN
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: O
Product: CCc1nc2c(C)cc(NN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine. (2.0 g), and hydrazine hydrate (15 mL) was heated to 120° C. for 24 hours. Concentration and purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH) gave 1.80 g of 5-hydrazino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine. Reduction in methanol (50 mL) under 1 atm. H2 with W-2 Raney nickle (1 mL, 50% dispersion/water) at RT for 48 hours gave the title compound (1.44 g) after purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:9][C:10](=[O:27])[C:11]([CH3:26])=[CH:12][C:13]1[CH:18]=[C:17]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:16]2=[CH:15][CH:14]=1)[CH3:8]>[Fe].O>[CH2:7]([O:9][C:10](=[O:27])[C:11]([CH3:26])=[CH:12][C:13]1[CH:18]=[C:17]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:16]2=[CH:15][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)C(C)=Cc1ccc2cc([N+](=O)[O-])ccc2c1
Agent: [Fe]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc2cc(N)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
Into 30 ml of benzene, 2.0 g (7 mmol) of 3-(2-nitro-benzo[d]phenyl)-2-methyl-2-propenoic acid ethyl ester were dissolved; and, with 1.73 g of iron powder (Koso Chem. Co.) and 2.5 ml of distilled water being added thereto under stirring at room temperature, temperature was raised, so that a reaction was carried out for 1.5 hours at 70° C. After the completion of the reaction, insoluble matters were filtered out, and the filtrate was added to 100 ml of water. The resulting solution was extracted twice with 100 ml of ethyl acetate; and thus obtained ethyl acetate solution was successively washed with water, an aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution. The washed solution was dried on sodium sulfate anhydride; and, after sodium sulfate was filtered out, the filtrate was concentrated. Thus obtained oily product was refined by a silica gel column chromatography (silica gel; developing solvent: ethyl acetate/hexane=1/5), whereby 1.4 g of the aimed compound were obtained as an oily product (yield: 77%).
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]2[C:13]/1=[CH:12][C:11]([N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[CH:10][CH:9]=2.CN(C)C=O.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>CCOCC>[O:19]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([N:14]3[CH:15]=[CH:16][CH:17]=[CH:18]3)=[CH:10][CH:9]=2)/[C:4](=[CH:3]/[NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])/[C:5](=[O:20])[NH:6]1
Reactant: NCCCC(=O)O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)CCCN/C=C1\C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-4-(methoxymethylene)-6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione (201 mg, 0.75 mmole), dimethylformamide (5 mL), and 4-aminobutanoic acid (78 mg, 0.75 mmole) is stirred at room temperature for 1 hour. The reaction mixture is diluted with ether, filtered, washed with fresh ether and dried to give a beige solid, 215 mg, (84%), mp 230-40° C. dec; MS (ES+): m/z 338.1 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:16]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: BrCc1ccccc1
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol), benzyl bromide (0.178 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: N[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N([O-])=O.[Na+].[BrH:15]>O1CCOCC1.O.[Cu]Br>[Br:15][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccc(F)c1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 2-amino-3-fluorobenzonitrile (17.07 g, 0.125 mol) in 1,4-dioxane (20 ml) was added 48% aqueous hydrobromic acid (200 ml) and the solution was cooled to 0° C. before adding dropwise a solution of sodium nitrite (9.95 g, 0.144 mol) in water (22 ml) over 35 min so that the temperature did not rise above 3° C. The resulting mixture was stirred at 2–3° C. for 2 h then poured onto a cooled (5° C.) solution of copper(I) bromide (26.98 g, 0.188 mol) in 48% hydrobromic acid (100 ml). The mixture was stirred for 10 min then heated to 50° C. over 1 h. The mixture was cooled to ambient temperature, diluted with water (1 l) and extracted with diethyl ether (2×500 ml). The combined organic extracts were washed with 1 M aqueous Na2SO3 (500 ml), then saturated aqueous NH4Cl (200 ml), dried (MgSO4), and evaporated to give a brown oil/solid. Purification by chromatography (silica gel, 10% EtOAc/isohexane) and trituration of a mixed fraction with isohexane afforded 13.22 g (53%) of 2-bromo-3-fluorobenzonitrile as a pale yellow solid: 1H NMR (360 MHz, CDCl3) δ 7.62–7.68 (1H, m), 7.74–7.85 (1H, ddd, J 9, 9, 1), 7.74–7.85 (1H, ddd, J 8, 1, 1).
Reaction SMILES: [H-].[Na+].C(OCC)(=O)[CH2:4][C:5]([O:7]CC)=[O:6].Br[CH2:15][C:16]1[O:20][C:19]([CH3:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>CN(C)C=O.O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2[N:18]=[C:19]([CH3:21])[O:20][C:16]=2[CH2:15][CH2:4][C:5]([OH:7])=[O:6])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reaction time: 0.17 h

Procedure:
60% Sodium hydride in oil (0.6 g) was added portionwise to a solution of diethyl malonate (4.8 g) in N,N-dimethylformamide (50 ml). The mixture was stirred for 10 minutes and a solution of 5-bromomethyl-4-(4-chlorophenyl)-2-methyloxazole (4.30 g) in N,N-dimethylformamide (20 ml) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was dissolved in ethanol (30 ml), 2N sodium hydroxide (50 ml) was added, and the mixture was refluxed for 30 minutes, concentrated and washed with ethyl ether. The aqueous layer was acidified with hydrochloric acid and the precipitate was taken up with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was dissolved in pyridine (30 ml). The solution was refluxed with stirring for an hour and the pyridine was distilled off. To the residue was added water and the mixture was adjusted to pH 2 with hydrochloric acid. The resulting crystalline precipitate was collected by filtration to give 4-(4-chlorophenyl)-2-methyloxazole-5-propionic acid, yield 2.50 g (62.8%). Recrystallization from ethanol gave needles, yield 1.85 g (46.5%), m.p. 211°-212° C.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([K])[CH3:9].Cl>O>[C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: CC[K]
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Product: CCOC(=O)CC(=O)O
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Ethyl potassium malonate (25.0 g, 0.15 mol) was suspended in water (15.6 ml) and cooled in an ice bath. Concentrated HCl (12.5 ml) was added dropwise over 30 min, then the mixture was stirred for a further 10 min. The precipitate was filtered, then washed twice with ether. The filtrate was separated and the aqueous phase was extracted with ether. The combined ethereal solutions were dried (MgSO4) and evaporated to afford, as an oil, monoethyl hydrogen malonate (19.2 g, 99%) which was dried under vacuum overnight (or 50°/1 mm for 1 h) prior to use.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:39])[C@@H:25]([NH2:38])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:39])[CH:25]([NH:38][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:31][CH:32]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Yield: 23.1 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester (Bachem, 0.284 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give the title compound as a white solid (0.096 g, 29%), mp=87-90° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].Cl>O1CCOCC1>[NH2:27][C@H:22]1[C:23]2[C:19](=[C:18]([C:16]3[S:17][C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])=[CH:14][CH:15]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)s2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CC[C@H]4N)s2)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)thiophen-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate (15 mg, 0.03 mmol) in 1,4-dioxane (1 mL) was added 4N HCl solution in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 16 h. Solvent was evaporated the resulting solid was dissolved 1:1 DMSO:MeOH (1 mL) and purified by preparative HPLC to afford 10 mg (90%) of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile 225 as a white solid. LCMS-ESI (m/z) calculated for C23H22N2OS: 374.2; found 358.1. [M-NH2]+, tR=2.69 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:44])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[C:38]([OH:43])[CH:39]=5)[CH:34]=4)[N:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:49][CH2:50][O:51][CH3:52]>CN(C=O)C>[C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:44])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[C:38]([O:43][CH2:49][CH2:50][O:51][CH3:52])[CH:39]=5)[CH:34]=4)[N:25]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc5cc(O)ccc5c4)cc4ccnn34)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2cc(-c3cc4ccnn4c(Nc4ccc(NC(=O)c5ccc(CNC(=O)OC(C)(C)C)cc5)cc4)n3)ccc2c1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of (4-{4-[5-(6-hydroxy-naphthalen-2-yl)-pyrazolo[1,5-c]pyrimidin-7-ylamino]-phenylcarbamoyl}-benzyl)-carbamic acid tert-butyl ester (compound A3)(120 mg) in DMF (3 ml) are added NaH (8 mg) and 2-bromoethylmethylether (0.019 ml). The mixture is stirred overnight and after extraction the crude product is purified by silica gel flash chromatography. A nearly colorless solid (68 mg) in 52% yield is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:13]([C:15]([C:21]#[N:22])=[C:16](SC)[S:17][CH3:18])#[N:14]>>[C:13]([C:15]([C:21]#[N:22])=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:14]
Reactant: NCCSCc1ncccc1Cl
Reactant: CSC(SC)=C(C#N)C#N
Product: CSC(NCCSCc1ncccc1Cl)=C(C#N)C#N

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine with 1,1-dicyano-2,2-bis-methylthioethylene by the procedure of Example 1(b)(i) yields 1,1-dicyano-2-methylthio-2-[2-((3-chloro-2-pyridyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [Na].[C:2]1(=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.I[CH2:16][CH2:17][CH3:18]>CO>[CH2:16]([S:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][C:2]2=[O:14])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[CH2:17][CH3:18]
Reactant: CCCI
Reactant: O=C1CCc2ccc(S(=O)O)cc21
Agent: [Na]
Solvent: CO
Product: CCCS(=O)(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.25 g of sodium is dissolved in 50 ml of anhydrous methanol. 1.96 g of indan-1-one-6-sulfinic acid (see above) are added in portions and the mixture is stirred for 30 min at room temp. 1.87 g of 1-iodopropane are then added and the mixture is stirred for 4 hours at reflux temp. For completion of the reaction, the mixture is concentrated in vacuo, treated with 5 ml of iodopropane and 10 ml of toluene and heated to reflux for 2 hours. It is then concentrated, the residue is extracted by shaking with water and CH2Cl2, the org. phase is dried and concentrated, and the residue is purified by column filtration (SiO2 ; cyclohexane/ethyl acetate=2/1). 6-(Propane-1-sulfonyl)indan-1-one of melting point 100° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[N:29][S:30][N:31]=2)[N:28]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[N:29][S:30][N:31]=3)[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Clc1ccc2nsnc2n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nsnc4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 5-chloro[1,2,5]thiadiazolo[3,4-b]pyridine (82 mg, 0.48 mmol) as starting materials. LRMS (APCI) calc'd for (C19H16F2N5O2S2) [M+H]+, 448. found 448.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:33])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:19]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:15]=2)[N:10]=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([CH3:37])=O.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[C:1]([NH:5][C:6](=[O:33])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH:35]([CH3:37])[CH3:34])[CH2:21][CH2:20]3)[CH:15]=2)[N:10]=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCNCC3)cc2c1=O
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCCN(c2ccc3nc(-c4cccc(Cl)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)CC1
Yield: 47 %

Procedure:
N-tert-Butyl-2-[2-(3-chlorophenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 1a) (17 mg, 0.03 mmol), anhydrous acetone (30 μL), sodium cyanoborohydride (3 mg, 0.03 mmol) and glacial acetic acid (12 μL, 0.21 mmol) in anhydrous THF (0.15 mL) was heated in a microwave at 130° C. for 10 minutes. The resulting mixture was purified by preparative TLC on silica gel with DCM:MeOH:NH4OH (40:2:1, v/v) as eluent to give N-tert-butyl-2-[2-(3-chlorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 5a) (7.1 mg, 0.014 mmol, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]1[C:17](=[O:18])[N:16]([O:19][C:20](ON2C(=O)CCC2=O)=[O:21])[C:14](=[O:15])[CH2:13]1>C(#N)C>[CH2:12]1[C:17](=[O:18])[N:16]([O:19][C:20]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH:3]=2)=[O:21])[C:14](=[O:15])[CH2:13]1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: O=C(Nc1ccc2ncccc2c1)ON1C(=O)CCC1=O

Procedure:
6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate was synthesized according to the following procedure. Acetonitrile (500 ml, Baker analyzed HPLC grade) was distilled to azeotropically remove any water present. The first 50 ml of acetonitrile was discarded. 6-Aminoquinoline (1.5 g, 10 mmol, Aldrich Chemical Co.) was dissolved in 50 ml of acetonitrile and placed in an addition funnel. Di(N-succinimidyl) carbonate (DSC; 3 g., 12 mmol, Fluka Chemical Co.) was dissolved in 100 ml. of acetonitrile and heated to reflux with stirring. The aminoquinolino solution was added dropwise to the refluxing solution over a period of about 30 minutes.