Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH2:19]([S:24]([CH:27]1[CH2:30][NH:29][CH2:28]1)(=[O:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:19]([S:24]([CH:27]1[CH2:30][N:29]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:28]1)(=[O:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCS(=O)(=O)C1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCS(=O)(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.9 mL), 3-(pentylsulfonyl)azetidine hydrochloride (39 mg, 0.17 mmol; which may be prepared as described in Step 4), DIPEA (106 μL, 0.64 mmol), DMAP (2 mg, 0.02 mmol) and EDAC (36 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: 90/10 DCM/MeOH) then triturated in pentane with a drop of acetone to give the title compound (12 mg, 19%) as a white solid.
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]23N(C)[CH:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15][CH2:14]3)=[N:5]1.C(=O)([O-])[O-].[K+].[K+].C[N:29](C)C=O>O>[C:2]([N:1]1[CH:15]2[CH2:16][CH2:17][CH:18]1[CH2:19][CH:13]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][N:5]=1)[CH2:14]2)#[N:29]
Reactant: CN1C2CCCC1(c1n[nH]c3ccccc13)CC2
Reactant: CN(C)C=O
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#CN1C2CCC1CC(c1n[nH]c3ccccc13)C2
Reaction time: 3 h

Procedure:
Cyanogen bromide (10 g) was added in one portion to a suspension of (1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (11 g) and potassium carbonate (12 g) in dimethylformamide (250 ml) at room temperature. The mixture was stirred for 3 hours after which it was diluted with water, and extracted with ethyl acetate (3×300 ml). The combined organic solution was washed with brine, dried over MgSO4, filtered and concentrated to leave 11 g of an oil. Crystallization from DCM:hexane provided 3.1 gm of a solid, m.p. 199°-201° C. Recrystallization from ethanol gave 1.15 g of crystals, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19](Br)[S:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:31]#[C:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: C#Cc1ccccc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3csc(Br)n3)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(c2ccc(NC(=O)c3csc(C#Cc4ccccc4)n3)cc2)C1
Temperature: 150 °C

Procedure:
2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was dissolved in tetrahydrofuran (2 ml), and phenylacetylene (52 mg), triethylamine (52 mg), triphenylphosphine (17 mg), bis(triphenylphosphine)palladium dichloride (89 mg) and copper (I) iodide (9.6 mg) were added. The reaction mixture was heated at 150° C. in a microwave apparatus for 3 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 416.55 (C24H24N4OS); MS (ESI): 417 (M+H+).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[Cl:13][C:14]1[S:18][N:17]=[C:16]([OH:19])[CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[S:18][N:17]([CH2:3][CH2:2][C:1]([C:5]2[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)=[O:4])[C:16](=[O:19])[CH:15]=1
Reactant: C=CC(=O)C1=CC(=O)C=CC1=O
Reactant: Oc1cc(Cl)sn1
Solvent: Cc1ccccc1
Product: O=C1C=CC(=O)C(C(=O)CCn2sc(Cl)cc2=O)=C1

Procedure:
A stirred solution of 2-acryloyl-1,4-benzoquinone (1.0 g, 0.007 mole) and 5-chloro-3-hydroxyisothiazole (0.81 g, 0.006 mole) in 20 ml of toluene was heated at 80° C. for 4 hours. Upon cooling, the precipitate which formed during the reaction period was removed by filtration and recrystallized from ethyl acetate/acetone mixture. A gray/tan solid was obtained; 0.85 g; mp 181°-183° C.; IR (KBR) 1635 cm-1 (broad);NMR (acetone-d6) δ7.35 (s,1H); 7.15 (d 1H); 6.85 (d 1H); 6.35 (s,1H); 4.2 (t,2H); 3.52 (t,2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>O.CCO.ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[N:11][OH:12])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1(C)CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(=NO)CC1
Temperature: 25 °C

Procedure:
A solution of 4,4-dimethylcyclohexanone (30 g, 0.238 mol), hydroxylamine hydrochloride (32.8 g, 0.476 mol) and sodium acetate (39.0 g, 0.476 mol) in H2O/EtOH (720 mL, 5/1) was heated under reflux. The reaction was monitored by TLC and cooled to room temperature upon completion. It was diluted with dichloromethane (500 mL). The organic layer was separated, washed with brine (100 mL) and dried over Na2SO4. Solvent was removed under reduced pressure, and 4,4-Dimethylcyclohexanone oxime was obtained as colorless solid, which was used in the next step without further purification.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30]N)[C:25]=2[F:32])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]3[C:3]4[CH2:4][C:5]5[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=5)[C:2]=4[NH:30][C:26]=3[C:25]=2[F:32])=[CH:22][CH:23]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(C#N)cc2C4)cc1

Procedure:
A sample of 1-oxo-indan-5-carbonitrile (133.5 mg, 0.85 mmol) (Example 74, step 1) and (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (250.4, 0.85 mmol) are reacted together as in example 1, step 3 followed by purification by UV triggered reverse phase HPLC to afford the title compound as a white solid. LC/MS calculated for [M+H]+ C26H21FN2: 381.2, found: 381.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:33]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)=[NH:34]>C(O)C.C(OCC)C.[Pd]>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:33]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[NH:34])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CSC(=N)c1cccs1
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Agent: [Pd]
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4cccs4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (150 mg, 0.378 mmol) was dissolved in anhydrous ethanol (10 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon, (40.3 mg, 0.0378 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) showed complete conversion to 8a 1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzoimidazol-5-ylamine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (10 mL) and the ethanolic solution of the amine 8a is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (140 mg, 0.491 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 67 hours. The solution was diluted with diethyl ether (80 ml) and cooled in and ice bath resulting in the formation of an off-white precipitate that was collected on a sintered glass funnel and washed with ether. The hygroscopic solid was solubilized on the funnel in methanol and the solvent collected and evaporated to yield crude solid. The solid was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 8. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford yellow residue 10 N-[1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzo-imidazol-5-yl]-thiophene-2-carboxamidine. Yield: 94 mg (52.2%). 1H NMR (DMSO) δ: 0.82 (t, 6H, J=7.1), 1.29 (t, 3H, J=7.0), 2.45 (q, 4H, J=7.0), 2.45-2.50 (m, 2H), 3.98 (q, 2H, J=7.0), 4.07-4.13 (m, 2H), 4.22 (s, 2H), 6.31 (br s, 2H), 6.72 (d, 1H, J=7.7), 6.88 (d, 2H, J=8.7), 6.99 (s, 1H), 7.08-7.11 (m, 1H), 7.17 (d, 2H, J=8.4), 7.35 (d, 1H, J=8.4), 7.59 (d, 1H, J=5.1), 7.72 (d, 1H, J=3.4); MS (ESI): 476 (MH+, 100%)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:17])=O.CN(C)C=O.P(Cl)(Cl)(Cl)=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]#[N:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (5.0 g) and N,N-dimethylformamide (100 ml) was added phosphoryl chloride (3.33 g) at room temperature and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (4.10 g, 89%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propionitrile. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 63-64° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9](=[S:11])=S.[CH3:12][NH:13][NH2:14]>O.C1COCC1>[CH3:12][N:13]([C:9](=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH2:14]
Reactant: CNN
Reactant: Brc1ccccc1
Reactant: S=C=S
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CN(N)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
Bromobenzene (1.6 g, 10 mmol) was added into 25 ml anhydrous THF solution containing magnesium powder (0.3 g, 12.5 mmol), and refluxed for 2 hr. After it was cooled, the clear reaction solution was added into carbon disulfide (1 ml, 16.8 mmol) at 0° C., and stirred for 30 min at rt. The resulting mixture was then added into methylhydrazine (1.6 ml, 30 mmol) at 0° C., and stirred for another 2 hours. To this solution was added water (15 ml) and extracted with EtOAc (30 ml×3). The organic solution was concentrated to minimum volume, and subjected to silica gel column chromatography (eluant: 1:3-1:1 ethyl acetate:hexanes) to give thiobenzoic acid N1-methyl hydrazide (0.72 g, total yield: 48%). 1H NMR (CDCl3) δ 3.3 (s, 3H), 6.0 (s, 2H), 7.3-7.4 (m, 5H); ESMS calcd (C8H10N2S): 166.1. found: 167.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:17])[CH2:18][OH:19])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)N)cc1OC
Reactant: OCC1CO1
Solvent: CC(C)O
Product: COc1ccc(CC(C)NCC(O)CO)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(3,4-dimethoxyphenyl)-2-propylamine (20.0 g, 0.10 m) in isopropanol (20 ml) is heated to 50° C. while a solution of glycidol (5.0 g, 0.067 m) in isopropanol (5 ml) is added over 15 minutes. The mixture is stirred at 50° C. for 0.5 hours and then at 70° C. for 16 hours. The solvent is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with 10% MeOH-CHCl3 saturated with NH3 to yield (I) weighing 14.37 g (80%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=1[F:11]
Reactant: COC(=O)CBr
Reactant: Fc1cc2cc[nH]c2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
6-Bromo-5-fluoro-1H-indole (10 g, 46.7 mmol) was dissolved in DMF (100 mL) and cooled to 0° C. in an ice bath before the addition of sodium hydride, 60% dispersion in mineral oil (3.74 g, 93 mmol) and methyl 2-bromoacetate (8.59 mL, 93 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was cooled with an ice bath once again then quenched with water (50 mL). The aqueous layer was extracted with DCM (3×200 mL). The organics were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to afford the title compound (10.209 g). LCMS (A): m/z (M+H)+ 286/288, C11H9BrFNO2 requires 285/287 (acidic).
Reaction SMILES: B(F)(F)F.CCOCC.[BH4-].[Na+].[C:12]1([S:18]([N:21]2[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][N+:28]([O-])=O)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([S:18]([N:21]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22]2)(=[O:19])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])C=Cc1ccn(S(=O)(=O)c2ccccc2)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1ccn(S(=O)(=O)c2ccccc2)c1

Procedure:
Boron trifluoride etherate (17.7 g) was added under nitrogen with ice-cooling to sodium borohydride (3.94 g) suspended in tetrahydrofuran (150 ml). After stirring at room temperature for fifteen minutes 2-(1-phenylsulphonyl-3-pyrrolyl)-1-nitroethylene (5.78 g) (prepared according to Synthetic Communications, 15 (1), 71-74 (1985)), dissolved in tetrahydrofuran (80 ml) was added dropwise. The mixture was refluxed overnight, quenched by the addition of ice-water, acidified with 5M hydrochloric acid and refluxed for a further two hours. The aqueous layer was washed with ether and the amine liberated by the addition of 0.880 ammonia solution which was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give pure product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:50][CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][O:42][CH2:43][CH2:44]2)=[O:33])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: NCCN1CCOCC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN4CCOCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-morpholino-1-ethanamine (66 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (41 mg, yield 27%).
Reaction SMILES: O[C:2]([CH:4]([C:6]1[CH:19]=[CH:18][CH:17]=[C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:7]=1)[CH3:5])=[O:3].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.C([O:36][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][S:43](=[O:46])(=[O:45])[NH2:44])C>ClCCl>[C:9]([C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:2]([NH:44][S:43]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([OH:47])=[O:36])(=[O:45])=[O:46])=[O:3])[CH:19]=[CH:18][CH:17]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CCOC(=O)CCCCCS(N)(=O)=O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C(=O)NS(=O)(=O)CCCCCC(=O)O)c1cccc(C(=O)c2ccccc2)c1
Yield: 46.3 %

Procedure:
To a suspension of racemic ketoprofen (3.81 g, 15.0 mmol) in dichloromethane (50 ml) were added HOAt (2.04 g, 15.0 mmol) and EDC (2.88 g, 15.0 mmol), and the mixture was stirred until a clear solution resulted. To this solution was added a solution of 6-sulfamoylhexanoic acid ethyl ester (2.23 g, 10.0 mmol) and DI PEA (2.56 ml) in dichloromethane, and the mixture was stirred at room temperature for 3 d. The mixture was washed with 1N aqueous HCl, dried over MgSO4, and concentrated. Purification by column chromatography yielded 2.0 g (44%) of the title compound. An analytical sample was obtained by preparative HPLC.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=1.C1C[O:30]CC1>>[CH3:26][S:25]([C:21]1[N:20]=[C:19]([N:14]2[C:15]3[C:11](=[C:10]([CH2:9][O:5][CH2:4][CH2:3][S:2][CH3:1])[CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)[CH:24]=[CH:23][N:22]=1)=[O:30]
Reactant: CSc1nccc(-n2ccc3c(CBr)cccc32)n1
Reactant: C1CCOC1
Reactant: CSCCO
Agent: [H-]
Agent: [Na+]
Product: CSCCOCc1cccc2c1ccn2-c1ccnc(S(C)=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-methylsulfanyl-ethanol (0.29 mL, 3.36 mmol) was dissolved in THF (5 mL), cooled in an ice bath, and NaH (148 mg, 3.7 mmol) was the added portionwise. After 30 min, a suspension of 4-bromomethyl-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indole (750 mg, 2.24 mmol) in THF (5 mL) was added, and the mixture was stirred at RT overnight. The mixture was then concentrated in vacuo, and the residue purified using flash chromatography on a silica column, eluting with hexane:ethyl acetate 4:1 to 3:7 to yield 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(2-methylsulfanyl-ethoxymethyl)-1H-indole (390 mg).
Reaction SMILES: [C:1]1([N:7]2[C:10](=[O:11])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH:20][CH3:21]>C(#N)C>[CH3:19][N:20]([CH3:21])[C:10]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:9][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:18])=[O:11]
Reactant: O=C1N(c2ccccc2)C(=O)N1c1ccccc1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C(=O)N(C(=O)Nc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
In 30 ml of acetonitrile, 0.025 mole of 1,3-diphenyl-1,3-diazetidine-2,4-dione was added, then 4.5 ml (0.05 mole) of dimethylamine aqueous solution (50%) was added dropwise under stirring. The reaction was continued at 50° C. for 0.5 hours and the solvent was removed by distillation under a reduced pressure to obtain a residue. The residue was recrystallized from ethanol to obtain 5.4 g (yield 76%) of 1,1-dimethyl-3,5-diphenylbiuret having a melting point of 105°-107° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19]1.C([BH3-])#N.[Na+]>>[C:29]([CH:28]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][CH:19]=1)([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(Cc1c[nH]c2ccccc12)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
As described in Example 1, react 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid and ethyl indole-3-pyruvate with sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([C:23]([O-:25])=[O:24])[C:3]([O:5][C:6]1[C:7]([F:22])=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])=[C:10]([C:13]#[N:14])[C:11]=1[NH2:12])=O.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:13]([C:10]1[C:11]2[N:12]=[C:3]([C:2]([CH3:26])([CH3:1])[C:23]([O:25][CH2:38][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:24])[O:5][C:6]=2[C:7]([F:22])=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH3:15])#[N:14]
Reactant: Cc1c(C#N)c(N)c(OC(=O)C(C)(C)C(=O)[O-])c(F)c1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C(=O)OCc3ccccc3)nc2c1C#N
Yield: 856.5 %

Procedure:
A mixture of 4-amino-5-cyano-2-fluoro-6-methylbiphenyl-3-yl 2,2-dimethylmalonate (I-63) (500 mg, 1.12 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.112 mmol) and toluene (20 ml) was heated under reflux for 2 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, then the solvent was evaporated away to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (411 mg, 86%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:21])[O:19][CH2:20][C:13]=12.Cl>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:13]2[N:12]=[CH:17][CH:16]=[CH:15][C:14]=2[C:18]([OH:21])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1OCc2ncccc21
Reactant: Oc1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccnc1COc1ccc(Br)cc1
Temperature: 165 °C

Procedure:
32 g (185 mmol) of 4-bromophenol are treated in methanol with 33.32 g (185 mmol) of 30% solution of sodium methoxide in methanol. The solvent is eliminated and the residue mixed with 5.0 g (37.00 mmol) of furo[3,4-b]pyridin-5(7H)-one (prepared according to Synthesis, 1997, 113-116). The system is stirred at 165° C. for 30′ (at first the mixture melts, afterwards solidifies). Once at room temperature, the solid is dissolved in excess water, adjusted at pH 7-8 with 2N HCl and extracted two times with dichloromethane. The aqueous layer is adjusted at pH 5-6 with more 2N HCl and the solid that precipitates is filtered, washed with water and dried. The yield is 6.6 g (58%).