Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][OH:13])=[O:6])[CH2:3][CH2:2]1.[S:25](Cl)([CH3:28])(=[O:27])=[O:26].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:28][S:25]([O:13][CH2:12][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:6])(=[O:27])=[O:26]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (1.12 g, 3.39 mmol) obtained in Example 112 and mesyl chloride (0.293 ml, 3.73 mmol, 1.1 eq.) were dissolved in THF (22 ml), and a solution of triethylamine (0.615 ml, 4.41 mmol, 1.3 eq.) in THF (2 ml) was added dropwise over 10 min with stirring at 0° C. The reaction mixture was stirred at 0° C. for 50 min. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with 10% brine and saturated brine. The aqueous layers were each extracted with ethyl acetate (50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (1.31 g, 3.21 mmol, 94.6%).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])C.C([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)(=O)C(C)C.[C:19](OCC)(=[O:21])C.C(=O)(O)O.[Na]>C1CCCCC1.O1CCCC1>[OH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:19](=[O:21])[CH:3]([CH3:1])[CH3:4]
Reactant: CC(C)C(=O)Oc1ccccc1Br
Reactant: [Li]C(C)CC
Reactant: CCOC(C)=O
Agent: O=C(O)O
Agent: [Na]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C(=O)c1ccccc1O
Temperature: -75 °C
Reaction time: 2 h

Procedure:
100 ml of sec-butyllithium at 1.4 M in cyclohexane were added dropwise to a solution of 31.59 g (130 mmol) of 2-bromophenyl isobutyrate in 300 ml of tetrahydrofuran at −85° C. under nitrogen. The reaction medium was maintained for 30 minutes at approximately −75° C. and was then left to gently return to ambient temperature. After 2 hours, a little ethyl acetate was added, followed by approximately 400 ml of a 1 M aqueous sodium dihydrogen carbonate solution. The organic phase was recovered, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. 23.97 g of an orange oil were obtained and purified on silica cake. The residue obtained was chromatographed on a prepacked silica column (eluent heptane/ethyl acetate). 4.3 g of product were obtained in the form of a yellow oil. Yield=20%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)NC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@H](CC(=O)O)Nc1ccc(C#N)c(Cl)c1
Product: Cl

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-[(1-methylethyl)amino]butanoate (0.33 g, 0.94 mmol) in CH2Cl2 (2 mL) was treated with TFA (1 mL) for 1.5 h and the reaction was evaporated thoroughly. The residue was treated with 4N HCl in dioxane (4 mL) and then concentrated (this step was done twice) and the crude product was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:28][CH2:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: Nc1ncnc2sc(CBr)c(-c3ccc([N+](=O)[O-])cc3)c12

Procedure:
A suspension of Example 1D (500 mg, 1.75 mmol) in benzene (50 mL) was treated with NBS (340 mg, 1.91 mmol) and AIBN (50 mg), stirred at reflux for 3.5 hours, and concentrated. The concentrate was absorbed onto silica gel and purified by flash column chromatography with ethyl acetate to provide 330 mg of a 1.7:1 mixture of the desired product and recovered starting material.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:4].[CH3:20]COCC>C(O)(=O)C>[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:4])[CH3:20]
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CCOCC
Solvent: CC(=O)O
Product: CC(=O)OC1c2ccccc2Oc2ccccc21
Reaction time: 1 h

Procedure:
To 15 g. of 9-(N-methylcarbamoyloxy)xanthene, suspended in 200 ml. of dry ether, was added 18 ml. of glacial acetic acid with stirring. After one hour, the lower acid layer was removed. The ether phase was then cooled, neutralized with cold aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from benzene-hexane to give 9-acetoxyxanthene, m.p. 109°-112° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([O:11]C)[C:4]=1[OH:13])#[N:2].B(Br)(Br)Br.O.Cl>ClCCl>[C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([OH:11])[C:4]=1[OH:13])#[N:2]
Reactant: COc1cc(C#N)cc(C#N)c1O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(O)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 2,4-dicyano-6-methoxyphenol in 20 ml of dichloromethane 20 ml of 1 molar solution of BBr3 in dichloromethane was added. The solution was stirred overnight at room temperature. Water and hydrochloric acid were added and the mixture was extracted with dichloromethane. The solvent was evaporated. Yield 0.8 g (50%), m.p. 300° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ru].O>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Solvent: O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 2 liter Parr autoclave was charged with 100 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 375 grams Isopar™ G, 25 grams dionized water, and 50 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts) placed under a screen in the bottom of the autoclave. The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 100° C. with stirring at approximately 1200 rpm and held for 4 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that complete conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 100% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 19.8:1.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[CH2:9]=[CH:10][CH3:11]>[Cr].[Co]>[CH3:8][C:1]1[CH:6]=[C:5]([CH:10]([CH3:11])[CH3:9])[CH:4]=[C:3]([CH3:7])[CH:2]=1
Reactant: C=CC
Reactant: Cc1cccc(C)c1
Agent: [Co]
Agent: [Cr]
Product: Cc1cc(C)cc(C(C)C)c1

Procedure:
A reaction was carried out using a Hastelloy C autoclave having an inside volume of 6,000 mL and equipped with an electromagnetic stirrer, a baffle plate, a gas blowing port and a liquid feed port in the same manner as that in Example 1. For the reaction, 2,003 g (18.9 moles) of metaxylene, 943 g (47.1 moles) of anhydrous HF and 715 g (17.0 moles) of propylene were used. After the reaction was terminated, the reaction mixture was fed at a rate of 300 mL per hour together with 600 g per hour of benzene to a distillation column (column internal pressure: 0.38 MPa, 122° C.) in which benzene was recirculated. A benzene solution of 3,5-dimethylcumene was separated and collected from the bottom of the column, while discharging BF3 from the top and HF from a discharge port below the condenser. The benzene solution of 3,5-dimethylcumene obtained from the bottom of the column was condensed using an evaporator and then distilled (column internal pressure: 0.0133 MPa, stage number: 12, a reflux ratio: 10) to obtain 1,925 g of desired 3,5-dimethylcumene (distillation temperature: 129° C.). The purity was 99.2% and isolation yield was 76%.
Reaction SMILES: [CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:20])[C:10]([Cl:19])=[C:11]([S:15]C(=O)C)[CH:12]=3)[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:20])[C:10]([Cl:19])=[C:11]([SH:15])[CH:12]=3)[C:7]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Sc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C2CCCC2)Cc2cc(S)c(Cl)c(Cl)c2C1=O
Reaction time: 0.33 h

Procedure:
To a solution of 300 mg of 5-acetylthio compound prepared in (2) in the mixture of 1.3 ml of methanol and 0.6 ml of tetrahydrofuran was dropped 1.35 ml of 5% aqueous solution of sodium hydroxide and the mixture was stirred for 20 minutes at ambient and then concentrated under reduced pressure. 2 ml of water was added to the residue and the mixture was acidified to pH 1 with 1N hydrochloric acid under cooled with ice. The mixture was extracted with diethyl ether and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 210 mg of the title compound as crude product having following physical data.
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([CH3:16])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([S:7][C:8]1[N:9]=[C:10]([CH3:16])[CH:11]=[C:12]([CH2:14][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1nc(C)cc(C=O)n1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCSc1nc(C)cc(CN2CCCC2)n1
Reaction time: 24 h
Yield: 28.2 %

Procedure:
2-Hexylsulfanyl-6-methyl-pyrimidine-4-carbaldehyde (0.1 g, 0.42 mmol) was dissolved in ethanol (1 mL) and acetic acid (0.1 mL). Then pyrrolidine (0.07 mL, 1 mmol) and sodium cyanoborohydride (26 mg, 0.4 mmol) were added slowly at 20° C. and stirring continued for 24 h. The reaction mixture was evaporated to dryness and dissolved in a minimal amount of DMF (0.8 mL) and directly purified by preparative HPLC chromatography on a YMC combiprep ODS-AQ column (75×20 mm iD, S-5 μM, 12 nm) with an acetonitrile-water gradient. One obtained 34.7 mg (28%) of a yellow liquid. MS: m/z=294 (M+H).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:10][CH2:11][CH2:12][Cl:13])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)(CCBr)C#N)C=CC=CC=1.[N:38]12[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[CH2:42][NH:41][CH2:40][CH2:39]2.N1CCCCC1>>[ClH:13].[ClH:13].[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:10][CH2:11][CH2:12][N:41]2[CH2:42][CH:43]3[N:38]([CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:39][CH2:40]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCCCl)(c1ccccc1)c1ccccc1
Reactant: C1CCN2CCNCC2C1
Agent: N#CC(CCBr)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Product: Cl
Product: N#CC(CCCN1CCN2CCCCC2C1)(c1ccccc1)c1ccccc1

Procedure:
Substitution of an equivalent quantity of 2,2-diphenyl-5-chlorovaleronitrile for the 2,2-diphenyl-4-bromobutyronitrile, and 1,4-diazabicyclo[4.4.0]decane for the piperidine used in Example 22, and substantial repetition of the procedure detailed therein, affords 2,2-diphenyl-5-(1,4-diazabicyclo[4.4.0]dec-4-yl)valeronitrile dihydrochloride, melting at about 233° - 238° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22][OH:23].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N:13]([CH3:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:21][CH2:22][O:23][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(N(C)c4ccccc4)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A solution of 2-{5-methyl-2-[4-(methyl-phenyl-amino)-phenyl]-oxazol-4-yl}-ethanol (91 mg, 0.30 mmol) in CH2Cl2 (4.0 mL) was treated with para-toluenesulfonyl chloride (68 mg, 0.36 mmol), triethyl amine (0.20 mL) and a few crystals of DMAP. The resulting mixture was stirred at room temperature for 14 h and was quenched with water (0.2 mL). The mixture was purified directly by silica gel column chromatography (40% EtOAc/hexanes) to yield the title compound (120 mg, 83%). MS (ESI) m/z 463.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.[CH3:26][NH2:27]>>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:16])=[C:9]([C:4]2[N:5]=[C:6]([NH:27][CH3:26])[N:7]=[C:2]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=3)[N:3]=2)[CH:14]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(CO)cc1
Reactant: CN
Product: CNc1nc(Nc2ccc(CO)cc2)nc(-c2cc(Cl)ccc2C)n1
Yield: 81 %

Procedure:
The reaction of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine and 4-aminobenzyl alcohol using the method described in Example 67 and using methylamine in place of ammonia provided the title compound (81% yield). 1H NMR (acetone-d6) δ 8.75, 8.62 (2br s, 1H), 8.02-7.82 (m, 3H), 7.41-7.28 (m, 4H), 6.83 (br s, 1H), 4.62-4.59 (m, 2H), 4.10-4.05 (m, 1H), 3.05, 3.01 (2s, 3H), 2.67, 2.59 (2s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N:8]=[C:9]=S)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([NH:8][C:9]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:6][CH:7]=1
Reactant: Cc1cc(N=C=S)ncc1Cl
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To 5-chloro-2-isothiocyanato-4-methylpyridine (0.37 g, 2.0 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.7 mL, 5.0 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B of Example 17) (0.47 g, 2.0 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.94 mL, 6.0 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5-chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.19 g, 0.61 mmol, 30.3% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.79 (s, 1H), 8.08-8.15 (m, 2H), 6.78 (s, 1H), 3.82 (d, J=8.55 Hz, 2H), 3.55 (d, J=10.38 Hz, 2H), 2.93-3.02 (m, 5H), 2.71-2.80 (m, 5H), 2.66 (t, J=7.63 Hz, 4H), 2.23-2.29 (m, 7H), 1.94-2.02 (m, 2H), 1.92 (s, 1H), 1.86 (s, 2H), 1.53-1.62 (m, 5H), 1.41-1.49 (m, J=12.55, 9.88, 7.02, 2.29 Hz, 2H). MS (LC/MS) R.T.=0.72; [M+H]+=307.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([C:13]2([F:16])[CH2:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[O:17][CH3:18].CN([CH:22]=[O:23])C.C(=O)(O)[O-].[Na+]>C1COCC1>[F:16][C:13]1([C:11]2[CH:10]=[CH:9][C:8]([O:17][CH3:18])=[C:7]([CH:12]=2)[CH:22]=[O:23])[CH2:15][CH2:14]1
Reactant: CN(C)C=O
Reactant: COc1ccc(C2(F)CC2)cc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2(F)CC2)cc1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.7M solution in hexane, 3.42 ml) was added at −78° C. to a solution of 2-bromo-4-(1-fluorocyclopropyl)-1-methoxybenzene (1.88 g) in THF (62 ml), followed by addition of a solution of DMF (650 μl) in THF. After the reaction mixture was stirred at −78° C. for 30 minutes, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.00 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22]2)[N:3]=1
Reactant: NCC1CCc2ccccc2N1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCC2CCc3ccccc3N2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(aminomethyl)-1,2,3,4-tetrahydroquinoline hydrochloride and DBU in DME. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[C:11](=[O:12])[N:10]([CH2:13][CH:14]2[O:16][CH2:15]2)[C:8](=[O:9])[N:7]1[CH2:17][CH:18]1[O:20][CH2:19]1)[CH:3]1[O:5][CH2:4]1>[Cl-].[Na+]>[CH2:2]([N:6]1[C:11](=[O:12])[N:10]([CH2:13][CH:14]([OH:16])[CH2:15][Cl:1])[C:8](=[O:9])[N:7]1[CH2:17][CH:18]1[O:20][CH2:19]1)[CH:3]1[O:5][CH2:4]1
Reactant: O=c1n(CC2CO2)c(=O)n(CC2CO2)n1CC1CO1
Reactant: Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=c1n(CC(O)CCl)c(=O)n(CC2CO2)n1CC1CO1

Procedure:
A total of 36.5 g of 10% hydrochloric acid was added dropwise at 40° C. to a solution of 26.9 g (0.1 mole) of 1,2,4-triglycidyl urazole (TGU) in 700 ml of 10% aqueous sodium chloride solution so slowly that the pH-value could be kept constant at pH 5. The addition was over after about 70 minutes. Thereafter the reaction mixture was extracted 4 times with 250 ml of methylene chloride and the methylene chloride distilled off.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: COCCNCCOC
Product: COCCN(CCOC)c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1
Yield: 84 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)amide (Intermediate 17) and bis(2-methoxyethyl)amine (Aldrich), the title compound was obtained as a white solid in 84% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([N:19]([CH3:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH:11]=2)=[CH:6][CH:5]=1)(=O)C.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[O:33]=[C:28]1[NH:29][C:30](=[O:32])[C:31](=[CH:1][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])[CH:11]=3)=[CH:8][CH:9]=2)[S:27]1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)c1ccc(-c2cccc(CC(=O)N(C)c3ccccc3)c2)cc1
Product: CN(C(=O)Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)c1ccccc1
Yield: 70 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 1 g (4 mmol) of 2-(4′-acetylbiphenyl-3-yl)-N-methyl-N-phenylacetamide with 460 mg (4 mmol) of 2,4-thiazolidine dione, 1.2 g (71%) of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[N:14]#[C:15]Br.C(#N)C>CCOCC.C(OCC)(=O)C>[CH2:7]1[C:8]2=[C:13]3[C:12](=[CH:11][CH:10]=[CH:9]2)[C:2]([NH:1][C:15]#[N:14])=[CH:3][CH:4]=[C:5]3[CH2:6]1
Reactant: N#CBr
Reactant: Nc1ccc2c3c(cccc13)CC2
Solvent: CCOCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CNc1ccc2c3c(cccc13)CC2
Reaction time: 8 h

Procedure:
5-aminoacenaphthene (7.0 g, 41.4 mmol) was dissolved in a mixture of ether (100 mL) and ethyl acetate (25 mL). To this solution was added 5.2 mL of a 5 M solution of cyanogen bromide in acetonitrile (25.6 mmol of cyanogen bromide). The solution was stirred overnight, with the gradual appearance of gray precipitate. The solid was removed by filtration (the hydrobromide of 5-aminoacenaphthene) and the resulting filtrate concentrated in vacuo to afford a semi-solid residue. Ether (60 mL) was added to the residue and the mixture was stirred overnight. The solid was removed (more hydrobromide of 5-aminoacenaphthene) and the filtrate concentrate to approximately 20 mL and then diluted with warm cyclohexane (15 mL). Upon standing at room temperature, off-white crystals were deposited. They were collected, washed with cyclohexane-ether (1:1) and dried in vacuo to give 1.5 g of pure product, mp: 163-65° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]([Cl:26])([Cl:25])[C:11]([NH:13][C:14](=[O:24])[NH:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:12].C(OCC)C>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:18]1[S:17][C:16]([NH:15][C:14]([NH:13][C:11](=[O:12])[C:10]([Cl:9])([Cl:25])[Cl:26])=[O:24])=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)c1ccsc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(=O)c1cc(Br)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
N-Bromosuccinimide (1.56 g, 8.8 mmol) was added to a solution of 2-[3-(2,2,2-trichloro-ethanoyl)-ureido]-thiophene-3-carboxylic acid amide (2.9 g, 8.8 mmol) in acetic acid (30 mL) and chloroform (10 mL) at room temperature. The resulting solution was stirred under nitrogen with an aliquot was taken for LC-MS every 10 min. After 30 min., the LC-MS showed no remaining starting material. Diethyl ether (80 mL) was added to the solution and the resulting precipitate was filtered and dried under vacuum to give the above titled compound as a light brown solid (3.5 g, 8.55 mmol, 97% yield).