Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3cccc([N+](=O)[O-])c3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)c1
Yield: 90.4 %

Procedure:
3 g of 10-(3-nitrobenzylidene)-5H-imidazo-(1,2-a]indeno[1,2-e]pyrazin-4-one are hydrogenated at atmospheric pressure and at 50° C. in the presence of 10% palladium-on-charcoal in 100 ml of dimethylformamide. After 20 hours of reaction, the reaction medium is filtered on Celite. The insoluble material is washed with 1 liter of dimethyl sulphoxide and the filtrate is concentrated to dryness under reduced pressure. After drying of the yellow powder thus obtained (5 mmHg; 0.65 kPa) at 65° C., 2.5 g of 10-(3-aminobenzyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained, the melting point of which is greater than 260° C. (Analysis, C20H16N4O.0.52 H2O.0.30 DMSO; % calculated C: 73.16; H: 4.91; N: 17.06; % found C: 73.2; H: 5.1; N: 17.2).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:19][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccccc1CBr
Yield: 80 %

Procedure:
A solution of compound 18b (4.5 g, 30 mmol), NBS (5.9 g, 33 mmol) and AIBN (0.5 g, 3 mmol) in CCl4 (20 mL) was refluxed overnight. The mixture was taken up in H2O (20 mL) and extracted with DCM (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by CC to give the compound 18c (5.5 g, 80% yield).
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]([OH:9])=[CH:7][CH:6]=[N:5]1)[CH3:3].C(N(CC)CC)C.[O:17]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25](Cl)=[O:26])=[N:18]1.CC(C)(O)C#N>C(Cl)(Cl)Cl>[CH2:2]([N:4]1[C:8]([OH:9])=[C:7]([C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:22]([C:19]3[CH:20]=[CH:21][O:17][N:18]=3)[C:23]=2[CH3:35])[CH:6]=[N:5]1)[CH3:3]
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1-c1ccon1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(-c3ccon3)c2C)c1O
Temperature: 25 °C

Procedure:
Separately 0.38 g of 1-ethyl-5-hydroxypyrazole hydrochloride was dissolved in 10 ml of chloroform, and 0.52 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 5 ml of a chloroform solution containing the previously obtained 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for an hour. To the reaction mixture were added 0.26 g of triethylamine and 0.05 g of acetone cyanohydrin to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the obtained residue. The produced crystals were separated by filtration to give 0.18 g of the title compound as white crystals. m.p. 85~88° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[S:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:19]2[CH2:20][CH2:21][S:16][CH2:17][CH:18]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCSCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C2=CCSCC2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture consisting of 17 g (0.082 mol) of 2,4-di-tert-butylphenol, 4.8 g (0.041 mol) of tetrahydrothiopyran-4-one and 5 ml of acetic acid is melted together and is then saturated, with stirring, with hydrochloric acid gas at 40-45° C. After stirring for 12 hours at room temperature, the reaction mixture is diluted with toluene and washed with water, sodium chloride solution and sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary-evaporator. The residue is crystallised from methanol, affording 9.2 g (74%) of 2,4-di-tert-butyl-6-(3,6-dihydro-2H-thiopyran-4-yl)phenol, m.p. 115-119° C. (compound (104), Table 1).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[Na+].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]#[N:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(O)C.O>[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([NH:28]/[N:29]=[C:8](\[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])/[C:9]([O:11][CH3:12])=[O:10])=[CH:26][CH:27]=1)(=[O:21])=[O:20]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CS(=O)(=O)c1ccc([N+]#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(=O)/C(=N\Nc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by addition of 4-(methylsulfonyl)benzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduce pressure to yield 7.0 g (83%) of (E)-dimethyl 2-(2-(4-(methylsulfonyl)phenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 357 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH2:12](O)[CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:15][CH2:14][CH2:13][CH2:12][O:6]2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: OCCCO
Reactant: COc1cc(Br)cc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc(C2OCCCO2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 3-bromo-5-methoxybenzaldehyde (3.93 g, 18.2 mmol), propane-1,3-diol (1.6 mL, 21.8 mmol) and p-toluenesulfonic acid monohydrate (0.104 g, 0.54 mmol) in anhydrous toluene (100 mL) was brought to reflux for 18 h under nitrogen. During this time water was removed using a Dean-Stark apparatus. After this time the reaction was cooled to rt, washed with 5% aqueous Na2CO3 solution (50 mL) and dried over anhydrous Na2SO4. The reaction was concentrated under reduced pressure to give 2-(3-bromo-5-methoxyphenyl)-1,3-dioxane (4.80 g, 96%) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[C:18]1([S:24]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-nitro-4-chloroaniline (500 mg) and pyridine (2.1 ml in methylene chloride (10 ml), benzenesulfonylchloride (1.2 ml) was added dropwise at 0° C. under an atmosphere of argon. The reaction mixture was stirred for 3 days at room temperature. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The reside was recrystallized from AcOEt-hexane mixture solvent to give the by-product. The mother liquor was concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-hexane) and recrystallized from AcOEt-hexane mixture solvent to give the title compound (175 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:18])[C:3]=1[CH3:19].[CH2:20]([O:23][C:24](Cl)=[O:25])[CH2:21]Cl.CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:15]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:2]([N:1]2[CH2:21][CH2:20][O:23][C:24]2=[O:25])[C:3]([CH3:19])=[C:4]([Cl:18])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: O=C(Cl)OCCCl
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(N2CCOC2=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) and 4-dimethylaminopyridine (53 mg, 0.43 mmol) in tetrahydrofuran (1 mL) was added 2-chloroethyl chloridocarbonate (0.041 mL, 0.40 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 1.0 M potassium tert-butoxide in tetrahydrofuran (0.79 mL) at 0° C., and the resulting mixture stirred at room temperature for 2 hours, then quenched with aq. ammonium chloride, extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and evaporated. The filtrate was applied on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (14 mg, 10%). LCMS calculated for C18H16ClFNO3 (M+H)+: m/z=348.1. found: 348.0.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH:10]([OH:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]([CH2:9][CH:10]([OH:13])[CH2:11][NH:12][CH:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:30][CH:31]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CC(O)CN)c1ccccc1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)CN(C)c1ccccc1
Yield: 54.7 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 1.55 g of 3-(N-methyl-N-phenylamino)-2-hydroxypropylamine (prepared as described in Preparation 90), 1.6 g of 5-[4-(2-oxopropoxy)benzyl]-thiazolidine-2,4-dione, 0.4 g of sodium cyanoborohydride and 50 ml of anhydrous methanol were used, to give 1.39 g of the title compound, melting at 115° C. to 125° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:18]=[CH:19][N+:20]([O-])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O.O1CCCC1.C(OCC)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:18][CH2:19][NH2:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(CCN)cc1OCc1ccccc1

Procedure:
To a suspension of 20 parts of lithium aluminum hydride in 444 parts of tetrahydrofuran and 177 parts of ethyl ether is added portionwise, over a 1 hour period, a warm solution of 56 parts of 3-benzyloxy-4-methoxy-β-nitrostyrene in 267 parts of tetrahydrofuran. The reaction mixture is refluxed for an additional 2 hours, then is cooled in ice and decomposed by adding 40 parts of water in 71 parts of tetrahydrofuran, followed by 40 parts by volume of a 25% by weight aqueous sodium hydroxide solution, followed by 40 parts of water. The salts are removed by filtration and the filtrate is dried over anhydrous calcium sulfate and stripped of solvent under reduced pressure to afford, as an oil, 3-benzyloxy-4-methoxyphenethylamine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[NH:3]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCCCCN1c2nc(-c3ccccc3)c(-c3ccccc3)cc2CCC1C
Reaction time: 2 h

Procedure:
To a microwave vial was added 2-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridine (step 2) (345 mg, 1.148 mmol) in NMP (1 ml) followed by ethyl 7-bromoheptanoate (0.671 ml, 3.45 mmol) and cesium carbonate (748 mg, 2.297 mmol). The resulting mixture was heated using microwave radiation at 160° C. for 2 h. Ethyl-7-bromoheptanoate (0.671 ml, 3.45 mmol) was added and heating continued for a further 2 h. The reaction mixture was partitioned between EtOAc and water and the organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded a yellow oil which was loaded onto a Isolute™ SCX-2 cartridge and eluted with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford racemate ethyl 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoate. Chiral separation of the mixture using Supercritical Fluid Chromatography afforded the individual enantiomers.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH:58]([CH3:60])[CH3:59])=[O:56]>C1(C)C=CC=CC=1>[CH:58]([O:57][C:55](=[O:56])[NH:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:43][CH2:44]3)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:60])[CH3:59]
Reactant: CC(C)OC(=O)Cl
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 78.2 %

Procedure:
Prepared from cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl)-amide bis hydrochloride (50 mg, 0.075 mmol), 44 mL (0.25 mmol) of DIPEA and 0.10 mL (0.1 mmol) of 1 M isopropyl chloroformate in toluene (Aldrich) as described in the procedure above to give 40 mg (78%) of a white solid. Preparative HPLC condition: YMC XTERRA, S5, 30×50 mm, gradient: 50% B to 100% B. 15 min. hold 2 min. flow rate 40 mL/min) NMR (300 MHz, CD3OD) δ. LC-MS (Method A, retention time: 3.32 min), MS m/z 682 (M++1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3)ccc21
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Benzoyl chloride (305 μL, 1.5 eq.) was added to a solution of 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (407 mg, 1.74 mmol) and triethylamine (1.2 mL, 5.0 eq.) in dichloromethane (5 mL) at 0° C. and the resulting mixture was stirred for 15 min. The reaction was then quenched by addition of sat. NaHCO3 and the mixture was extracted with 3×EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated and the product was purified by chromatography (20 to 100% EtOAc-hexanes) to give 5-benzoylamino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (588 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.CCN(CC)CC.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C1COCC1.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 32 %

Procedure:
To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (J Med Chem, 1995;38:3482) (0.50 g, 1.59 mmol) in THF (20 mL) under nitrogen was added Et3N (excess, 1.0 mL), a catalytic amount of DMAP and methacryloyl chloride (1.1 mol eq., 1.75 mmol, 171 μL) dropwise. The reaction was stirred at 25° C. for 1.5 hours over which time two further amounts (50 μL) of methacryloyl chloride were added. The reaction was then diluted with saturated NaHCO3 and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and chromatographed on silica gel eluting with CH2Cl2/EtOAc (1:1) to MeOH/CH2Cl2/EtOAc (5:45:50). Recrystallization from EtOAc gave N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]-2-methylacrylamide (195 mg, 32%) as a cream powder, mp 244-245° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22]Cl)#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)#[N:18]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: N#CCCN(CCC#N)SCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(SN(CCC#N)CCC#N)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 20 h

Procedure:
4.4 g (0.02 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 3.8 g (0.02 mole) of bis(cyanoethyl)aminosulfenyl chloride obtained in Example 31, and 4.7 g (0.06 mole) of pyridine were dissolved in 35 ml of methylene chloride, and the resulting solution was stirred for 20 hours at 25° to 30° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities. Yield: 6.2 g (82.7%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](N)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.C(O)C>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1ccc2ccc(N)cc21
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)n1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-methansulfonyl-6-amino indole (2.10 g, 10.0 mmol), prepared as described in Forbes, et al., J. Med. Chem. (1996) 39:4968, was suspended in 40 ml of water, then cooled in an ice bath. Concentrated sulfuric acid (3 ml) was added slowly dropwise. The mixture was warmed to room temperature for 5 min then cooled back down to 0° C. A solution of NaNO2 (Mallinckrodt, 0.76 g, 11.0 mmol) in 10 ml of water was added slowly and the resultant foam was treated with 10 ml of ethanol. The mixture was added in portions to a boiling solution of CUSO4 (J. T. Baker, 16.0 g, 0.1 mol) in 75 ml of water. After 15 min, the mixture was cooled. The brown solid which had formed was broken up with a glass stirring rod. NaHCO3 was added to neutralize the reaction and the product was extracted with ethyl acetate (2×100 ml). The extracts were dried (anhydrous MgSO4) and concentrated to give 1-methansulfonyl-1H-indol-6-ol (1.62 g), a brown oil which was used with out purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:42]4[C:38](=[CH:39][CH2:40][N:41]=4)[CH:37]=3)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4c(c3)=CCN=4)nc21
Reactant: CCOC(=O)C=C(Cl)c1ccccc1C
Product: CCOC(=O)C=C(c1ccccc1C)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21

Procedure:
The title compound was synthesized from 3-chloro-3-o-tolyl-acrylic acid ethyl ester and 7-[2-(2H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure outlined in Example 18, step (d), in a 35% yield of an E/Z isomeric mixture. 1H NMR (CDCl3) δ 7.46 (m, 0.6H), 7.30 (m, 4.8H), 7.10 (m, 1.6H), 7.03 (d, 0.6H, J=3.6 Hz), 6.94 (m, 1H), 6.85 (m, 0.4H), 6.70 (m, 1H), 6.53 (d, 0.8H, J=2.8 Hz), 6.47 (d, 0.2H, J=2.8 Hz), 6.30 (s, 0.2H), 5.82 (s, 0.8H), 4.39 (m, 2H), 4.10 (m, 2H), 3.78 (m, 2H), 3.22 (t, 2H, J=6.8), 2.75 (t, 2H, J=6.8), 2.07 (s, 2.4H), 2.02 (s, 0.6H), 1.94 (m, 2H), 1.53 (s, 9H), 1.05 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(O)C>[CH2:15]([N:17]([CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)Cc1nnc2nc(N)nc(N)c2n1
Temperature: 100 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg; 0.95 mmol) and diethylamine (2.00 mL) in absolute ethanol (2.0 mL) was heated to 100° C. in a sealed tube for 5 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 65 mg of yellow colored 3-Diethylaminomethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 4 as the trifluoroacetate salt.