Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][CH:17]([O:22]C)[C:18](OC)=O>N>[CH3:15][O:16][C:17]([CH:18]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)=[O:22]
Reactant: Nc1ncccc1Cc1ccccc1
Reactant: COC(=O)C(OC)OC
Agent: N
Product: COC(=O)C1Nc2ncccc2Cc2ccccc21
Yield: 337 %

Procedure:
A mixture of 2-amino-3-benzylpyridine (18.3 g, 99.4 mmol; crude) and methyl 2,2-dimethoxyacetate (22 g, 21.6 mmol, 1.9 eq.) in a 250 ml round-bottomed flask was treated at room temperature with concentrated, sulphuric acid (50 ml) by quick addition while stirring. A vigorous exothermic reaction took place. After stirring for 30 minutes the dark mixture was poured on ice water (1000 ml). Concentrated ammonia (25% aq.; 250 ml) was added to basify the mixture. Extraction with dichloromethane (2×150 ml). The combined organic layers were dried with Na2SO4. Evaporation under vacuum gave 10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-carboxylic acid methyl ester as a yellow foam (18.5 g, 72.8 mmol) in 73% yield. An analytically pure sample can be obtained by chromatography on silica gel. Rf=0.3 (EtOAc/n-heptane=1:1).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[C:5]2[CH2:20][CH2:21][CH2:22][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][C:36]2[NH:37][C:38]([C@@H:40]([NH2:42])[CH3:41])=[N:39][C:35]=2[CH:34]=1.ClCl>CN(C)C=O>[Cl:32][C:33]1[CH:44]=[CH:43][C:36]2[NH:37][C:38]([C@@H:40]([NH:42][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:6]4[C:5]5[CH2:20][CH2:21][CH2:22][C:4]=5[N:3]=[C:2]4[CH3:1])=[C:8]([C:16]([F:19])([F:17])[F:18])[CH:9]=3)[CH3:41])=[N:39][C:35]=2[CH:34]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1nc2c(n1-c1ccc(C(=O)O)cc1C(F)(F)F)CCC2
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(n1-c1ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc1C(F)(F)F)CCC2
Yield: 64 %

Procedure:
Prepared analogously to Example 1d from 4-(2-methyl-5,6-dihydro-4H-cyclopentaimidazol-1-yl)-3-trifluoromethylbenzoic acid, PFTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 64%; C24H21ClF3N5O (487.911); mass spectrum: (M−H)−=486/488 (chlorine isotope).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].[C:14]([Li])([CH3:17])([CH3:16])[CH3:15].O(C)[Li]>CCCCCC>[F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5]([C:14]([CH3:17])([CH3:16])[CH3:15])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Reactant: [Li]C(C)(C)C
Agent: [Li]OC
Solvent: CCCCCC
Product: CO[Si](CCC(F)(F)F)(OC)C(C)(C)C
Temperature: 0 °C
Yield: 110.9 %

Procedure:
Under nitrogen, a 500 ml Schlenk flask was cooled to 0° C. and charged with 150 ml hexane and 3,3,3-trifluoropropyl trimethoxy silane (0.075 mol, 15 ml). A nitrogen purged addition funnel was fitted to the flask and charged with tert-butyllithium (0.075 mol, 34 ml). This was added dropwise to the cooled flask creating a cloudy, white precipitate (LiOCH3). After addition (1 hour), the addition funnel was washed with 20 ml of hexane. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The flask was fitted with a reflux condenser and the reaction mixture refluxed for two hours. After cooling to room temperature, the reaction mixture was filtered through a medium porosity filter tube, using Celite diatomaceous earth and glass wool as a filtering aid. A white solid was collected, which weighed 11.13 g wet (theoretical=3.0 grams of LiOCH3). The hexane was removed from the filtrate to give 20.33 g of a clear yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].N12CCCN=C1CC[CH2:11][CH2:10][CH2:9]2.CC(C)=O.BrCCCBr>CN(C=O)C>[CH3:7][O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)CC#N
Agent: BrCCCBr
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CCC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
10 g (0.1 mol) of methyl cyanoacetate and 10 mL of anhydrous DMF were mixed under stirring for 10 minutes, followed by adding 33.4 g (0.22 mol) of 1,8-diazabicyclo[5,4,0] undec-7-ene (DBU) at 10-20° C. into the mixture, heating the mixture to 50° C. to allow reaction to take place for 15 minutes, moving the mixture to an ice bath (−5˜−10° C.) of a mixture of liquid nitrogen and acetone, and adding 20.4 g (0.10 mol) of 1,3-dibromopropane dissolved in 10 mL of anhydrous DMF into the mixture to form a reaction solution. The reaction solution was subjected to reaction at 25° C. for 15 minutes, and to further reaction at 70° C. for 30 minutes, followed by evaporating, extracting with CH2Cl2 and deionized water, collecting an organic layer from the extraction, evaporating, purifying using silica column chromatography (eluent: acetone/hexane=8/1), and re-evaporating to obtain a product of 8.74 g (0.063 mol, 62.85%) of 4.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[O:28][C:24]([C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=3)=[C:25]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[N:26]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(-c2nc(-c3ccccn3)c(Br)o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.75 g, 8.90 mmol), 2-[5-bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridine (1.9 g, 5.94 mmol), Pd(PPh3)4 (0.343 g, 0.297 mmol) and sodium carbonate (11.8 ml, 2 M, 23.74 mmol) in DMF (100 ml) was heated at 120° C. overnight. Then the DMF was removed under reduced pressure, and the resulting residue was purified on a silica gel column (ethyl acetate/hexane) to give the title compound. LC-MS m/e 422.23 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][C:11]([OH:17])([C:14]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=3)=[O:16])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C1(O)CCN(c2ncccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C1(O)CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
1-(3-Chloro-2-pyridinyl)-4-hydroxy-4-piperidinecarboxylic acid, EDCI (525 mg, 2.7 mmol), and 4-(trifluoromethyl)aniline in dichloromethane (10 mL) were combined at room temperature and stirred overnight. Standard work-up gave a crude product which was purified via chromatography (SiO2, ethyl acetate:hexanes, 1:9). 1H NMR (500 MHz, CDCl3) δ 8.90 (s(br), 1H), 8.20 (dd, 1H), 7.74 (d, 2H), 7.61 (m, 3H), 6.86 (dd, 1H), 3.80 (m, 2H), 3.18 (m, 2H), 2.50 (m, 2H), 1.78 (m, 2H); MS (ESI, M+H)+ 400.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([NH2:11])([CH3:10])[CH3:9]>>[CH3:9][CH:8]([N:11]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:10]
Reactant: O=C1CCCCC1
Reactant: CC(C)N
Product: CC(C)N=C1CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 600 g. cyclohexanone and 1 l. isopropylamine are added 500 g. Linde Type 3A molecular sieves. The mixture is allowed to stand overnight at room temperature, after which the isopropylamine is removed in vacuo at room temperature. The oily residue is 1-methyl-N-(cyclohexylidene)-ethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.[Cl:45][C:46]1[S:50][C:49]([CH2:51]Cl)=[CH:48][CH:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[Cl:45][C:46]1[S:50][C:49]([CH2:51][N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]3([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]3)[C:6]2=[O:11])=[CH:48][CH:47]=1
Reactant: O=C1Nc2ccc(F)cc2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ccc(Cl)s2)c2ccc(F)cc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 5′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 5-chloro-2-(chloromethyl)thiophene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (76%) as a colorless solid: mp 142-144° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.22-7.17 (m, 1H), 7.14-7.13 (m, 1H), 7.12-7.10 (m, 2H), 6.96 (d, 1H), 6.68 (s, 1H), 6.13 (s, 1H), 5.91 (d, 2H), 5.02 (ABq, 2H), 4.73 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 161.0, 157.8, 156.0, 149.0, 142.2, 138.3, 138.2 (d, 4JcF=7.0 Hz) 133.6 (d, 3JcF=33 Hz), 128.3, 127.8, 127.1, 119.5, 115.6 (d, 1JcF=93 Hz), 112.5 (d, 1JcF=100 Hz), 110.8 (d, 3JcF=32 Hz), 103.2, 102.0, 93.9, 79.8, 58.2 (d, 4JcF=7.0 Hz), 39.0; MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:7]=1)=[O:4].C(O)=O.ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>O>[C:11]1([N:8]2[CH2:9][CH2:10][C:6]([NH:5][CH:3]=[O:4])=[N:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)CC1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Solvent: O
Product: O=CNC1=NN(c2ccccc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 10.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared in Example 8) and 50.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to stand at room temperature for 3 hours. Water is added and the white crystals are collected by filtration. The solid is dissolved in dichloromethane. The solution is dried over magnesium sulfate and filtered through a hydrous magnesium silicate. The filtrate is evaporated in vacuo to give pink crystals. A 500 mg. portion of crude product is recrystallized from dichloromethane-hexane to give 403 mg. of the desired product as a white solid, m.p. 140°-141° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:42]=[CH:41][C:34]2[O:35][C:36]([CH3:40])([CH3:39])[O:37][CH2:38][C:33]=2[CH:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:22]1([S:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:28][C@@H:29]([C:31]3[CH:42]=[CH:41][C:34]4[O:35][C:36]([CH3:39])([CH3:40])[O:37][CH2:38][C:33]=4[CH:32]=3)[OH:30])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Reactant: O=S(=O)(c1ccc(C#CCCOCCCCCCBr)cc1)C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCC#Cc3ccc(S(=O)(=O)C4CCCC4)cc3)ccc2O1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
To a stirred solution of 1-{4-[(6-bromohexyl)oxy]but-1-ynyl}-4-(cyclopentylsulfonyl) benzene (280 mg) in DMF (10 ml) were added (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (WO 0266422 A1) (170 mg) and diisopropylethylamine (165 μl). The mixture was heated at 50° for 22 h before being allowed to cool to room temperature. The mixture was dissolved in EtOAC, washed with brine, dried (MgSO4) and evaporated to dryness. The residual oil was purified on a silica bond elut SPE cartridge (10 g), gradient 0% to 30% [MeOH-aqueous ammonia (10:1)] in DCM (Gradmaster™). The appropriate fractions were evaporated to give the title compound (127 mg) LCMS RT=2.87 min
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2.O[Li].O>C1COCC1.O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][NH:20][C:19]=1/[CH:18]=[C:10]1\[C:11](=[O:17])[NH:12][C:13]2[C:9]\1=[C:8]([C:7]#[C:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH:16]=[CH:15][CH:14]=2
Reactant: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)O)c21

Procedure:
Using Method F above, (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester (50 mg, 0.14 mmol) (from Example 8 above) was hydrolyzed with LiOH•H2O (118 mg, 2.8 mmol) in THF (3 mL) and water (3 mL) for 22 h. (Yield 40 mg, 85%).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1.C(=O)([O-])[O-].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO>[CH2:36]([O:35][C:33]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:10]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: CC(O)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-naphthalene-1-sulfonic acid piperidin-4-ylamide acetic acid salt 37 (290 mg, 0.74 mmol) in MeOH (10 mL) was added MP-Carbonate (1.45 g, 3.69 mmol, 2.54 mmol/g). After shaking at 25° C. for 1 h, the solution was filtered. To the resultant solution was added ethyl chloroformate (120 mg, 1.11 mmol). After stirred for another 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The crude material was purified by Flash column chromatography (CH2Cl2:MeOH) to provide 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38. LCMS showed m/z: 407 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][OH:13])[CH2:6][CH2:5]2.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CCc2cc(I)ccc2O1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2cc(I)ccc2O1
Temperature: 27 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A reaction mixture containing [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methanol (Example 8, 5 g, 17.2 mmol, 1.0 eq), tert-butyldimethylsilyl chloride (20.6 mmol, 1.2 eq), and imidazole (43 mmol, 2.5 eq) in anhydrous DMF (35 mL) was stirred at 27° C. overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column) providing the product in 79% yield; m/z=405 [MH=].
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[O:16].[ClH:17]>C(O)(=O)C>[Cl:17][C:12]1[NH:11][C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH3:5])[C:14]=2[N:13]=1
Reactant: Cl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Nitric acid (9 ml) was slowly added dropwise to a suspension of 3-methylxanthine (10 g) in acetic acid (180 ml) at 100° C., and the resulting white suspension was stirred at 100° C. for 30 minutes followed by 140° C. for 20 minutes. After cooling the reaction solution to room temperature, the solvent was removed by distillation at reduced pressure at 60° C. to give a yellow solid. The resulting yellow solid was washed with water, and recrystallization from 0.5 M hydrochloric acid gave a pale yellow solid. A suspension of the solid in concentrated hydrochloric acid (500 ml) was stirred at 110° C. for 15 minutes, then the reaction solution was cooled to room temperature, and the solvent was removed by distillation at reduced pressure to give a yellow-white solid. Recrystallization of the resulting solid from water gave 6.75 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:18]([Cl:19])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)[C:8]=1[NH2:9])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.O>C(COC)OC>[NH2:9][C:8]1[N:7]([C:10]2[C:18]([Cl:19])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)[N:6]=[CH:5][C:4]=1[C:1](=[S:29])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N
Solvent: O
Solvent: COCCOC
Product: CC(=S)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N

Procedure:
0.28 g (1 mmol) 4-Acetyl-5-amino-1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)pyrazole was dissolved in 5 ml dimethoxyethane and treated with 0.28 (0.6 mmol) Lawesson's reagent. After heating under reflux for 2 hours with stirring, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography. (Hexane/ethyl acetate 1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.[CH:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13](O)[CH:12]=1.B(O)(O)O>O>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([C:8]2[O:10][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:16]=3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: OB(O)O
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 12 h

Procedure:
68 g (0.5 mole of p-toluic acid were heated with 54.5 g (0.5 mole) of p-aminophenol and 2 g of boric acid in 750 ml of 1,2-methylnaphthalene and the water that formed was eliminated slowly by azeotropic destillation. After heating for 6 hours, 1 g of boric acid were added. After 12 hours, 16 ml of H2O (98%) passed over. The solvent was then removed until dryness, the residue was dissolved in 750 ml of ethanol, clarified with silica gel while still hot, and combined after filtration, while still hot, with 500 ml of H2O. After cooling and filtration with suction at room temperature and washing with aqueous ethanol, there were obtained 89.4 g (85.6% of the theory) of 2-p-tolyl-benzoxazole melting at 113° to 114° C. ##STR41##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].O.[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
In a similar manner, a solution of 46.4 g of 3-nitrobenzoyl chloride in 100 ml of tetrahydrofuran was added to a hot solution of 51.6 g of 5-aminotetrazole monohydrate in 1200 ml of tetrahydrofuran and 50 ml of water. The mixture was allowed to stand for 16 hours and then concentrated, and the resulting slurry was treated with water. The white solid was collected, washed with water and oven-dried to give 3-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 276° C. with decomposition.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(O)(=O)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=1[F:3])=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccc(I)cc1F
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(I)cc1F
Reaction time: 24 h
Yield: 99.2 %

Procedure:
A solution of bromine (2.74 mL, 53.18 mmol) in acetic acid (30 mL) was added dropwise to a solution of 1-(2-fluoro-4-iodo-phenyl)-ethanone (14.04 g, 53.18 mmol) in acetic acid (200 mL) at room temperature under an atmosphere of nitrogen and then stirred for 24 hours. The reaction was concentrated to near dryness in vacuo, diluted with ethyl acetate (200 mL) and basified with saturated aqueous sodium carbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered through a pad of silica gel and concentrated in vacuo to give 2-bromo-1-(2-fluoro-4-iodo-phenyl)-ethanone (18.10 g, 99%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].CN(C)C=O.[NH2:10][C:11](=[N:17][OH:18])[C:12](=[N:15][OH:16])[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:10][C:11](=[N:17][OH:18])[C:12](=[N:15][O:16][CH:2]([CH3:4])[CH3:3])[C:13]#[N:14]
Reactant: CC(C)I
Reactant: N#CC(=NO)C(N)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)ON=C(C#N)C(N)=NO
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
2.52 g (14.8 mM) of 2-iodopropane was added to an N,N-dimethylformamide solution (30 ml) of 2.00 g (15.6 mM) of 3-amino-2,3-bis(hydroxyimino)propionitrile. The mixture was cooled to 0° C. 2.05 g (14.8 mM) of potassium carbonate was added, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered to remove inorganic matter. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetete:hexane=1:2) to obtain 1.36 g (yield: 51%) of 3-amino-3-hydroxyimino-2-isopropoxyiminopropionitrile (compound No. 1-004).