Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)(O)[O-].[Na+].OO>O>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=O
Reactant: C=Cc1ccccc1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCCCCCCCCCCC
Product: c1ccc(C2CO2)cc1

Procedure:
To a mechanically stirred solution of styrene (0.1 mol), dodecane (0.01 mol), urea (2.08 mol), sodium bicarbonate (0.03 mol) in 50.0 ml of water at 20° C. is added 30% aqueous hydrogen peroxide (0.22 mol) drop-wise over a period of 5 h. After 5 h the organic layer of the reaction mixture was separated by a separating funnel. The aqueous layer was extracted with 4×20 mL diethyl ether. The combined organic layer was distilled to yield styrene oxide. The conversion to epoxide is 99% with selectivity 95%.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:15])([CH3:14])OCC>O1CCCC1>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:15])([CH3:14])[CH:1]=[CH2:2]
Reactant: CCO[Si](C)(C)CCCCBr
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[Si](C)(C)CCCCBr
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
A 3 l reactor was charged under nitrogen with 11 of vinyl magnesium bromide in THF (tetrahydrofuran) and 184 g of 4-bromobutyl-dimethyl-ethoxysilane were added slowly at room temperature. The mixture was then refluxed at 70° C. for 16 h. After cooling on ice, the mixture was quenched with 407 g of a 20% HBr (w/w) solution, after which it was stirred for another 1.5 h. The THF layers were separated from the aqueous layers and neutralized with aq. sodium hydrogen carbonate solution. The THF was evaporated and the residue was distilled in the presence of 1 g Pt/C to obtain 135.8 g (79.8%) of pure 4-bromobutyl-dimethyl-vinylsilane
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([CH3:31])([CH3:30])[CH2:22][C:23](=[O:29])[N:24]3[CH2:27][CH3:28])=[CH:19][C:18]=2[CH3:32])=[C:13]([O:33][C:34]([F:37])([F:36])[F:35])[CH:12]=1.C1(N(C2CCCCC2)C)CCCCC1.O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:6]([O:5][C:1](=[O:4])[CH:2]=[CH:3][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([CH3:31])([CH3:30])[CH2:22][C:23](=[O:29])[N:24]3[CH2:27][CH3:28])=[CH:19][C:18]=2[CH3:32])=[C:13]([O:33][C:34]([F:35])([F:36])[F:37])[CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(Br)cc3OC(F)(F)F)cc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(C=CC(=O)OC(C)(C)C)cc3OC(F)(F)F)cc21
Temperature: 80 °C

Procedure:
A sealed tube was charged with Pd[P(tBu)3]2 (4 mg, 0.0075 mmol), tert-butyl acrylate (0.03 mL, 0.18 mmol) and Compound 5B (68 mg, 0.15 mmol) in 1 mL of dry dioxane. To this was added dicyclohexyl methyl amine (0.04 mL, 0.18 mmol) and the tube was sealed and heated to 80° C. overnight. After the reaction was cooled, 3 mL of water was added and the solution was passed through a 5 mL solid phase extraction (SPE) column. The SPE was washed with dichloromethane and the collected eluant was stripped on the roto yap to give crude product Compound 5C which was further purified by flash chromatography (25% EtOAc/Hexane) to yield 45 mg (60%) of product. MS (electrospray): mass calculated for C28H32F3NO4, 503.23; m/z found 504.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC2=C1C(c1cccc(F)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc(F)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 44 %

Procedure:
A mixture of 9-(3-fluorophenyl)-3,4, 6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), sodium borohydride (6.1 g), ethanol (140 mL) and pyridine (50 mL) was heated at 70° C. overnight and cooled to room temperature. The solvent was removed and the resulting yellow solid was collected and washed well with water. Chromatography (ethyl acetate/hexane; 80/20) provided the title compound (2.1 g) as a yellow solid. Recrystallization from ethanol/hexane returned analytically pure light yellow solid, mp 249°-251° C.; NMR: 1.45-1.55 (m,3, CH2), 1.66-1.90 (m,5, CH2); 2.10-2.15 (m,4, CH2), 2.39-2.45 (m,2, CH2 (s,1, CH), 6.87-6.92 (m,2, Ar), 7.00 (d,1, J=7.8, Ar), 7.20-7.27 (m,1, Ar), 8.41 (s,1, NH); (CI, CH4) MS: m/z=298(M+1). Analysis for C19H20FNO: Calculated: C, 76.74; H, 6.78; N, 4.71; Found: C, 76.32; H, 6.71; N, 4.62.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[I-].C[N+]1C=CN([C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(OC(=O)N(C)c2ccccc2)n1
Yield: 59.6 %

Procedure:
A solution of 4,6-dimethyl-2-hydroxypyrimidine (0.37 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.46 g, 60% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:32]#[N:33])=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1B(O)O>>[C:32]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:37]2[CH:38]=[CH:39][C:40]([C:42]([F:45])([F:44])[F:43])=[CH:41][C:36]=2[O:35][CH3:34])=[N:3][CH:4]=1)#[N:33]
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(C#N)c3c2)c(OC)c1
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(C#N)c2cc(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
Example 240 was synthesized in a similar manner to Example 228, except that 1-chloro-4-cyano-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:EtOAc) to afford 4-cyano-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.07 (s, 1H), 9.29 (s, 1H), 8.52 (d, J=1.3 Hz, 1H), 8.06 (dd, J=1.8, 8.8 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 7.65-7.60 (m, 1H), 7.56 (s, 1H), 7.55-7.52 (m, 1H), 7.32 (d, J=4.5 Hz, 1H), 6.93 (d, J=4.5 Hz, 1H), 3.76 (s, 3H). m/z (ESI) 491.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C(O)(=O)C>[CH2:21]([O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
To a solution of 1-diphenylmethylazetidin-3-ol (300 mg, 1.3 mmol) in DMF (2.6 mL) at 0° C. under nitrogen was added NaH (60% in oil, 56 mg, 1.4 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with benzyl bromide (236 μL, 2.0 mmol). The mixture was allowed to warm to room temperature then heated to 80° C. overnight. The reaction mixture was cooled, acetic acid (20 drops) was added and the mixture concentrated under reduced pressure. The crude material was purified on column chromatography (eluent: Pentane/EtOAc, 95/5 to 70/30) to give the product (104 mg, 24%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:11]3[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[N:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28]Br)=[CH:22][CH:21]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][C:11]3([CH2:28][C:27]#[C:26][C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=4)[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[N:7][C:6]=2[CH:18]=1
Reactant: O=C1NC(=O)C(Sc2nc3cc(Cl)ccc3s2)S1
Reactant: Clc1ccc(C#CCBr)cc1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2ccc(Cl)cc2)(Sc2nc3cc(Cl)ccc3s2)S1

Procedure:
Prepared from 5-(5-chloro-benzothiazol-2-ylsulfanyl)-thiazolidine-2,4-dione, (III), Example 88 and [3-(4-chlorophenyl)-prop-2-ynyl]-bromide of formula (IX), Example 21: mp 187°-188° C.; Anal. Calc. for C19H10Cl2N2O2S3 : C, 49.04; H, 2.17; N, 6.02; Found: C, 48.94; H, 2.31; N, 6.21.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[CH2:24][CH3:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[CH2:24][CH3:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCCl)c(Br)c1
Reactant: C1CCNCC1
Solvent: CCOCC
Product: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCN2CCCCC2)c(Br)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
3-[3-bromo-4-(3-chloropropoxy)phenyl]-2-ethyl -4(3H)-quinazolinone (70 mg) was dissolved in piperidine (1 mL), and stirred at 80° C. for 5 hours. The reaction solution was diluted with diethyl ether, and insoluble matter was filtered off. The filtrate was concentrated, dried under vacuum, and the title compound (80 mg, 99%) was thus obtained as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl.O>[CH3:14][S:15]([O:13][CH2:12][CH2:11]/[CH:10]=[CH:9]/[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:17])=[O:16]
Reactant: OCC/C=C/c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
To a solution of Intermediate 2B (986 mg, 4.54 mmol) in CH2Cl2 (20 mL) was added TEA (1.899 mL, 13.63 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.531 mL, 6.81 mmol) was added dropwise. The reaction was stirred for 45 min at 0° C. then warmed to rt and diluted with water (20 ml) and CH2Cl2 (20 mL). The layers were separated, and the aqueous layer extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo to give Intermediate 2C (1.30 g, 97% yield). Intermediate 2C was carried onto the next reaction without further purification. HPLC/MS (Method D) RT=1.10 min, [M-MeSO3H+H]+199.1.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[N:23](C)S(N)(=O)=O.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:23])=[O:21])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(acetyl)-1-piperazinyl]carbonyl] (400 mg, 0.78 mmol), N,N-dimethylsulfamide (390 mg, 3.13 mmol) and DMAP (380 mg, 3.13 mmol) in dimethylacetamide (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (450 mg, 2.34 mmol). The reaction solution was stirred at 50° C. for 3 h, concentrated, purified by preparative HPLC (CH3CN/H2O with NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-(acetyl)-1-piperazinyl]carbonyl] (135 mg, 0.22 mol, 28%) as a yellow powder. 1HNMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.44 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.62-7.55 (m, 4H), 7.04 (s, 1H), 5.19 (br s, 1H), 4.34 (br s, 1H), 3.59-3.30 (m, 8H), 2.91 (s, 6H), 2.85-2.75 (m, 1H), 2.10-1.36 (m, 10H), 1.99 (s, 3H). LCMS: m/e 616 (M−H)−, ret time 1.57 min, column A, 2 minute gradient.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>CN(C=O)C>[N:33]1([C:31]([NH:30][C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:17]3[N:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:6][CH2:7][N:2]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)[N:16]=3)[CH2:25]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To it were added DIEA (190 μL, 1.10 mmol) and then acryloyl chloride (30 mg, 0.33 mmol). The mixture was stirred at RT for 20 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (499), as HCl salt (35 mg). LC-MS (ESI): m/z (M+1) 562.3. UV: λ=258, 329, 337 nm.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH2:29](I)[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:29]([N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12)[CH3:30]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), ethyl iodide (0.38 mL), potassium carbonate (0.13 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([NH:14][C:15](=[O:31])[CH2:16][C:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:20]=[N:19][CH:18]=2)[CH2:11][CH:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:35][O:34][C:32]([C@H:10]1[CH2:11][C@@H:12]([NH:14][C:15](=[O:31])[CH2:16][C:17]2[N:21]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)[CH:20]=[N:19][CH:18]=2)[CH2:13][NH:8][CH2:9]1)=[O:33]
Reactant: COC(=O)C1CC(NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CNC[C@H](NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(t-Butoxycarbonyl)-3-methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetylamino]piperidine (44.6 mg, 0.093 mmol) was dissolved in CH2Cl2 (6 mL). Trifluoroacetic acid (3 mL) was added and the solution was stirred at ambient temperature for 4 h. The solution was concentrated under reduced pressure to give the title compound without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([NH:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])=[CH:3][N:4]=1
Reactant: Nc1ccnnc1
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccnnc1

Procedure:
200 mg. of 4-aminopyridazine was suspended in 50 ml. of acetone. To the resulting suspension, 1.2 times the amount of phenyl isocyanate theoretically calculated was added and the mixture then reacted at room temperature overnight. The crystals formed were taken out by filtration. By recrystallization from an excess of methanol, N-(4-pyridazinyl)-N'-phenylurea was obtained (yield, greater than 80%); melting point higher than 250° C.
Reaction SMILES: [Na][Na].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].Cl[CH2:10][C:11]1([CH2:15][Cl:16])[CH2:14][O:13][CH2:12]1>>[Cl:16][CH2:15][C:11]1([CH2:10][O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:8][CH2:10][C:11]2([CH2:15][Cl:16])[CH2:14][O:13][CH2:12]2)[CH2:14][O:13][CH2:12]1
Reactant: ClCC1(CCl)COC1
Reactant: OCCCCO
Agent: [Na][Na]
Product: ClCC1(COCCCCOCC2(CCl)COC2)COC1

Procedure:
Reaction of the disodium salt of butane 1,4-diol with excess 3,3-bis-(chloromethyl)oxetane gives 1,4-bis-[(3-chloromethyl-3-oxetanyl)methyloxy]butane (10). This difunctional oxetane can be further substituted to give multioxetane compounds having various pendant groups. Substitution of the difunctional oxetane can be tailored so that the multioxetane compound can react with oxetane monomers having widely varying reactivity ratios. Reaction of 1,4-bis-[(3-chloromethyl-3-oxetanyl)methyloxy]-butane with sodium iodide gives 1,4-bis-[3-iodomethyl-3-oxetanyl)methyloxy]butane (11). Reaction of this diiodide with silver nitrate gives 1,4-bis-[(3-nitratomethyl-3-oxetanyl)methyloxy]butane (12), and with sodium azide it gives 1,4-bis-[(3-azidomethyl-3-oxetanyl)methyloxy]butane (13). ##STR10##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:19]([O:34][CH3:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:19]([O:34][CH3:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1C1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}piperidine-1-carboxylate (0.0446 g, 0.0937 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-yl)benzofuran-3(2H)-one (0.0312 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH:10]=[N:11][OH:12])=[CH:4][CH:3]=1.[Cl:19]Cl>CCOCC.C(Cl)Cl>[Cl:19][C:10](=[N:11][OH:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:7][CH2:6][C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ON=Cc1ccccc1OCc1ccc(Cl)cc1
Reactant: ClCl
Solvent: CCOCC
Solvent: ClCCl
Product: ON=C(Cl)c1ccccc1OCc1ccc(Cl)cc1

Procedure:
2-(4-Chlorobenzyloxy)benzaldehyde oxime (26.17 g) was dissolved in ether (200 ml) and methylene chloride (50 ml), and chlorine (6.0 ml) was introduced at -10° C. or below, and then the temperature was raised from -10° C. to room temperature over 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give crude α-chloro-2-(4-chlorobenzyloxy)benzaldehyde oxime. The resulting crude product was dissolved in acetonitrile (150 ml), a mixture of imidazole (17.02 g) and acetonitrile (100 ml) was added at room temperature over 15 minutes, and then the resulting mixture was stirred at 65 to 70° C. for 2 hours. After completion of the reaction, water and methylene chloride were added. The resulting crystals were separated by filtration to give 2-(4-chlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde oxime (11.05 g) as colorless crystals. mp. 196°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[C:21]([CH3:24])=[CH:22][N:23]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15](=[O:16])[NH:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[C:21]([CH3:24])=[CH:22][N:23]=1)(=[O:12])=[O:13])=[O:4]
Reactant: Cc1cnc(N)c(=O)n1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1ncc(C)n(C)c1=O
Yield: 47 %

Procedure:
A mixture of 1.218 g of 2-methoxycarbonylphenylsulfonyl isocyanate, 0.7 g of 3-amino-1,6-dimethylpyrazin-2-one and 15 ml of absolute dioxane is refluxed for 3 hours. The reaction mixture is evaporated to dryness and the residue is crystallized by treatment with acetone. 0.9 g of 3-[3-(2-methoxycarbonylphenylsulfonyl)-ureido]-1,6-dimethylpyrazin-2-one with a melting point of 192°-193° C. are thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CC(C)N
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and isopropylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.57 Hz, 6H) 2.44 (s, 3H) 4.13 (dd, J=14.15, 6.57 Hz, 1H) 7.66 (dd, J=8.08, 1.52 Hz, 1H) 7.74 (s, 1H) 7.75-7.85 (m, 1H) 8.07-8.28 (m, 1H) 8.45 (dd, J=19.70, 6.82 Hz, 3H) 8.84-8.98 (m, 1H) 12.97-13.37 (m, 1H). MS m/z [M+H]+ 362.2.