Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=1[CH2:20][CH:21]=[CH2:22])([CH3:3])[CH3:2].Cl>C(O)C.[Pd].CCOCC>[CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([CH3:3])[CH3:2]
Reactant: C=CCc1cc(OCCCC)ccc1OCCCNC(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCCOc1ccc(OCCCNC(C)C)c(CCC)c1
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A solution of N-isopropyl-3-(2-allyl-4-butoxy-phenoxy)propylamine (404 mg) in ethanol (15 ml) was hydrogenated at ambient temperature and pressure for 8 hours using a catalyst of palladium on carbon (10% w/w, 80 mg). The catalyst was removed by filtration and the filtrate evaporated to give a yellow oil. The oil was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 70:30:1 mixture of ethyl acetate, hexane and triethylamine to give an oil. The oil was dissolved in ether and excess ethereal hydrogen chloride was added until crystallisation began. The solid was collected by filtration and recrystallised from ethyl acetate to give N-isopropyl-3-(4-butoxy-2-propylphenoxy)propylamine (271 mg) as a white solid, m.p. 102 103° C.; microanalysis, found: C, 65.7; H, 10.2; N, 4.0%; C19H34NO2Cl. 0.25H2O requires: C, 65.5; H, 9.98; N, 4.02%; NMR ([CD3 ]2SO): 0.90(6H,m), 1.28(6H,d), 1.52(6H,m), 2.12(2H,m), 2.5(2H,m), 3.04(2H,m), 3.3(1H,m), 3.88(2H,t), 4.0(2H,t), 6.7(2H,t) and 6.85(1H,d); m/z 308 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:5]([CH2:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])[C:4]1=[O:33])[CH3:2].[OH:34]O.[OH-].[Na+]>C(O)C.O>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:5]([CH2:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]([NH2:29])=[O:34])[C:4]1=[O:33])[CH3:2]
Reactant: OO
Reactant: CCN1C(=O)C(Cc2cccc(C#N)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN1C(=O)C(Cc2cccc(C(N)=O)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Yield: 59 %

Procedure:
To a solution of 40 mg (0.91 mmol) of 3-[(1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)methyl]benzonitrile (IIcp) in 1 ml of ethanol, add under an inert atmosphere 27 μl (0.27 mmol) of 30% (m/m) H2O2 in water, 36 μl (0.018 mmol) of 0.5 M NaOH in water. Stir under reflux for 12 hours. Evaporate to dryness. Take up in a 25 ml of a water-ice mixture. Filter the solid, wash twice with 20 ml of water and once with 5 ml of ether. One obtains 24 mg of the abovenamed product as a white powder. Yield: 59%. M: 111–113° C. 1H-NMR (CDCl3, 200 MHz): d 1.10 (s, 3H, CH3), 3.50–3.75 (m, 6H, 1H —CH2Ph+1H —NCH2+CH+OCH3), 3.98–4.11 (m, 4H, 1H —CH2Ph+OCH3), 4.38–4.49 (m, 1H —NCH2), 5.91 (m, 1H exchangeable CO—NH2), 6.26 (m, 1H exchangeable CO—NH2), 6.66 (s, 1H Ar), 6.85 (s, 1H Ar), 7.30–7.86 (m, 9H Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@H:14]4[CH2:16][C@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.Cl.[NH2:21][C:22]([CH2:29][F:30])([CH2:27][F:28])[C:23](OC)=[O:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][CH2:27][C:22]([NH:21][C:17]([C:10]1[C:11]2[CH2:12][C@@H:13]3[CH2:16][C@@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])([CH2:29][F:30])[CH2:23][OH:24]
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Reactant: COC(=O)C(N)(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC(CO)(CF)CF)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (100 mg, 0.363 mmol), methyl 2-amino-3-fluoro-2-(fluoromethyl)propanoate hydrochloride (76 mg, 0.399 mmol) and triethylamine (0.101 mL, 0.725 mmol) in DMF (2 mL) was added HATU (138 mg, 0.363 mmol). The reaction was stirred at 50° C. for 2 h, then concentrated. The residue was purified by silica gel flash chromatography to give the title compound as a white solid. LCMS m/z=411.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.25 (td, J=7.8, 4.7 Hz, 1H), 2.24-2.30 (m, 1H), 2.79-2.84 (m, 1H), 2.89 (d, J=16.8 Hz, 1H), 2.99 (dd, J=16.4, 6.2 Hz, 1H), 3.89 (s, 3H), 4.81-5.12 (m, 4H), 7.22 (dd, J=5.3, 1.8 Hz, 1H), 7.51 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 8.36 (d, J=5.3 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10](=[O:27])[NH:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:26])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:36]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:27])[NH:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:26])=[O:8])=[CH:28][CH:29]=1)(=[S:36])[NH2:2]
Reactant: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C(N)=S)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (11.36 g), pyridine (500 ml), triethylamine (70 ml) and H2S gas were reacted to give isopropyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-3-methylphenoxyacetate (12.23 g) as a yellow solid: NMR Spectrum (DMSO-d6) 1.24 (6H, d), 2.28 (3H, s), 4.69 (2H, s), 5.01 (1H, m), 6.78 (1H, dd), 6.85 (1H, d), 7.77 (1H, d), 7.96 (2H, d), 8.05 (2H, d), 9.65 (1H, br s), 10.04 (1H, br s), 10.56 (1H, s), 11.11 (1H, s); Mass Spectrum m/Z 452 (M+Na)+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][N:14]=1
Reactant: CC(=O)c1cnc(C)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(2-methylpyrimidin-5-yl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: F[C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]SC2C=CC=CC=2)=[CH:6]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:30][C:28]1[CH:29]=[CH:2][C:3]([CH2:4][N:5]2[C:9]3=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]3[C:7]([CH2:18][N:34]3[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]3)=[CH:6]2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc2c(CSc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: O=C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A solution of methyl 3-(chloromethyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (24 mL, 2.0M in CH2Cl2, 48.3 mmol) [prepared as described in step 2 of example 40] was evaporated in vacuo to a residue. To this residue, anhydrous DMF (150 mL) and piperazin-2-one (386.4 mmol, 38.689, 8.0 eq.) were added followed by i-Pr2NEt (18.77 g, 145.2 mmol, 25.29 mL, 3 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 50° C. After stirring for 4 hours (50° C.) the reaction was judged to be complete by HPLC-MS analysis. The volatiles were removed in vacuo (ca. 2 torr, at 60° C.) to give a yellow residue. Saturated aqueous sodium bicarbonate (300 mL) was added. White solid precipitated out, and the mixture was sonicated for 30 min and cooled to 10° C. The solid was filtered, washed with cold water (50 mL), and dried in vacuo to afford 18.2 g (95%) of methyl 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—1.41 min, m/e=397.20 (M+H+, base). 1H NMR (300 MHz, DMSO-D6) d ppm 2.55 (t, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.74 (s, 2H) 3.84 (s, 3H) 5.56 (s, 2H) 7.16 (t, J=8.85 Hz, 2H) 7.34 (dd, J=8.19, 5.75 Hz, 2H) 7.71 (s, 1H) 7.81 (s, 1H) 8.41 (s, 1H) 8.93 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[CH3:33][N:32]1[C:25]2[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:24]=2)[CH2:30][C@@H:31]1[CH3:34]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(C(F)(F)F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:17])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Yield: 84.2 %

Procedure:
A solution of 1-bromo-3,5-dimethyl-benzene (1.0 g, 5.4 mmol, 1.0 eq), NBS (1.06 g, 5.94 mmol, 1.1 mmol) and AIBN (180 mg, 1.08 mmol, 0.2 eq) in CCl4 (20 mL) was stirred at reflux overnight. The reaction was then diluted with water and extracted with CH2Cl2. The organic extracts were combined and washed with aqueous NaHCO3, dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (Petroleum ether:EtOAc, 1:0 to 10:1) to give the title compound as a light yellow oil (1.2 g, 84%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][C:15]3[NH:14][C:13](=[O:17])[CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][C:15]2[NH:14][C:13](=[O:17])[CH:12]=[CH:11][C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Yield: 79.7 %

Procedure:
A mixture of 7-phenyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.19 g), aminoguanidine hydrochloride (0.092 g), concentrated hydrochloric acid (0.04 ml), water (0.04 ml) and ethanol (20 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 5-guanidinoimino-7-phenyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 99) (0.21 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][NH:9][CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16].[CH:17](=O)[CH2:18][CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:17][CH2:18][CH3:19])[CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16]
Reactant: Nc1c(Cl)cc2c(c1Cl)CCC1CNCC21
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN1CC2CCc3c(cc(Cl)c(N)c3Cl)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
6,8-Dichloro-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-7-ylamine (275 mg, 1.07 mmol) and propionaldehyde (81 μl, 1.12 mmol) were dissolved in tetrahydrofuran (25 ml). Acetic acid (90 μl, 1.6 mmol) and sodium trisacetoxyborohydride (340 mg, 1.6 mmol) were sequentially added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was dissolved in a 1 M NaOH solution (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted once more with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield the pure product (295 mg, 92%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH:17][NH2:18])=[O:16])[CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.Cl>ClCCl>[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH:17][NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)=[O:16])[CH2:10]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
A mixture of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid hydrazide hydrochloride, already prepared as described in Example 57 (C) (2.97 g, 11.2 mmol), 4-fluorobenzoic acid (1.68 g, 11.2 mmol), HOBT (1.5 g, 11.2 mmol), EDCI.HCl (3.2 g, 16.8 mmol) and dry triethylamine (5.43 mL, 39.5 mmol) in dry dichloromethane (80 mL) was kept under stirring overnight at ambient temperature, under nitrogen atmosphere. HCl 1N (80 mL) was then added and the phases separated. The organic layer was washed with HCl 1N (80 mL), with NaOH 1N (80 mL×2 times), then with water (80 mL). Evaporation of the organic solvent afforded a crude oil which was purified by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 98/2/0.2). The compound obtained after column chromatography was purified again by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 98/2/0.2) to provide the pure 4-fluoro-benzoic acid N′-[(S)-1-(4-fluoro-benzoyl)-piperidine-3-carbonyl]-hydrazide as a white solid (250 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[CH2:3]1.I[CH2:15][CH:16]([CH3:18])[CH3:17]>>[O:13]=[C:4]1[N:5]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:2](=[O:1])[CH2:3]1
Reactant: O=C1CC(=O)Nc2ccccc2N1
Reactant: CC(C)CI
Product: CC(C)CN1C(=O)CC(=O)N(CC(C)C)c2ccccc21

Procedure:
2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared following General Procedure 8-M using the product from Example 8-P, Step A and 1-iodo-2-methylpropane (Aldrich). Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to 1:1), then recrystallization from EtOAc/hexanes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[NH2:9][C:4]1[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: C1=CCNCC1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(N)nc(N2CC=CCC2)n1

Procedure:
300 g. of 2-chloro-4,6-diamino-s-triazine, 180 g. of 1,2,5,6-tetrahydropyridine and 170 g. of sodium bicarbonate are mixed in 1700 ml. of n-butanol and heated to reflux for 18 hours. The mixture is cooled and filtered. The residue is digested three times with hot chloroform and ethanol and filtered. The filtrates are combined and concentrated, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine having a melting point of 200°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][S:10]([CH2:12][CH2:13][NH2:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:15][S:16][C:17](S(C)=O)=[CH:18][N+:19]([O-:21])=[O:20]>>[CH3:15][S:16][C:17]([NH:14][CH2:13][CH2:12][S:10]([CH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11])=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: COc1cccnc1CS(=O)CCN
Product: COc1cccnc1CS(=O)CCNC(=C[N+](=O)[O-])SC

Procedure:
Reaction of 3-methoxy-2-(2-aminoethylsulphinylmethyl)pyridine with 1-methylthio-1methylsulphinyl-2-nitroethylene yields 1-methylthio-2-nitro-1-[2-((3-methoxy-2-pyridyl)methylsulphinyl)ethylamino]ethylene which, when reacted with 4-(4-aminobutyl)imidazole yields 1-nitro-2-[2-((3-methoxy-2-pyridyl)methylsulphinyl)ethylamino]-2-[4-(4-imidazolyl)butylamino]ethylene.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:42]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH:19]([OH:42])[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)Cc1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a stirred solution of methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (7.8 g, 22.27 mmol) in THF (40 mL) at −78° C. was added KHMDS (44.5 mL, 22.27 mmol) dropwise over 30 min. The mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (8.73 g, 33.4 mmol) in THF (50 mL) was added over 30 min and the reaction mixture was stirred for additional 2 h at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (40 mL). The reaction mixture was allowed to warm to room temperature and then diluted with ethyl acetate (200 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (4.2 g, 51.5%). 1H NMR (500 MHz, CHLOROFORM-d) δ 8.05-7.97 (m, 1H), 7.88 (dt, J=6.7, 1.8 Hz, 1H), 7.44-7.38 (m, 2H), 6.93 (s, 1H), 5.76 (s, 1H), 3.84 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH2:11][CH2:12][OH:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CCC1.[O-:25]Cl=O.[Na+]>C(#N)C.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O>[F:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:25])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCCn1cnc2cccc(F)c21
Reactant: [O-][Cl+][O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)Cn1cnc2cccc(F)c21
Temperature: 35 °C
Reaction time: 6 h

Procedure:
2-(7-fluoro-1H-benzimidazol-1-yl)ethanol (706 mg, 3.92 mmol) is suspended in 20 mL of acetonitrile and 15 mL of sodium phosphate buffer 1M (pH 6.5). The mixture is heated to 35° C. TEMPO (43 mg, 0.27 mmol) is added, followed by NaClO2 (80%, 887 mg, 7.84 mmol) dissolved in 4 mL of water and diluted bleach (2 ml of a 0.4% aqueous solution). The reaction mixture turns red-brown after the bleach addition. To drive the reaction to completion, if needed, more TEMPO (22 mg), NaClO2 (440 mg in 2 mL of water) and diluted bleach (1 mL) are added and the mixture stirred 6 hours at 35° C. After cooling at room temperature, the reaction is quenched by addition of saturated aqueous Na2SO3 (5 mL). The brown-red color disappears. The pH is adjusted to 8-9 by addition of NaOH 2M and the mixture is washed with ethyl acetate (2×). The organic layer is discarded and the aqueous phase is acidified with HCl 1M (up to pH 3). The desired product is crystallized in the aqueous phase as a white solid (537 mg, 70%). TLC: dichloromethane/methanol 10:1+5% triethylamine, Rf=0.33 (s.m.: Rf=0.56)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc[nH]c2c1

Procedure:
A solution of 1H-indole-6-carboxylic acid (10 g) in methanol (300 mL) was treated with concentrated sulfuric acid (0.5 mL) then heated on a steam bath for 10 hours. The solvent was removed under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution (150 mL) and dichloromethane (150 mL). The aqueous layer was further extracted twice with dichloromethane (150 mL). The combined organics were dried over sodium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (7:3, v/v) to give the title compound (7.4 g) as a white solid, m.p. 79-81° C. MS: 176 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]([Sn](C)(C)C)[N:17]=[N:16][N:15]=3)[CH:11]=[CH:10][C:9]=2[NH2:23])=[CH:4][CH2:3]1.[K+].[C:26]([C:28]1[N:29]=[C:30]([C:41]([O-])=[O:42])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=1)#[N:27].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH:11]=[CH:10][C:9]=2[NH:23][C:41]([C:30]2[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:28]([C:26]#[N:27])[N:29]=2)=[O:42])=[CH:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(-c3nnnn3[Sn](C)(C)C)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(-c3nnn[nH]3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 2-(4,4-dimethyl-cyclohex-1-enyl)4-(1-trimethylstannanyl-1H-tetrazol-5-yl)-phenylamine (as prepared in the previous step, 150 mg, 0.347 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 148 mg, 0.480 mmol), PyBroP (259 mg, 0.555 mmol) and DIEA (151 μL, 0.867 mmol) according to the procedure in Example 11, step (f) (103 mg, 57%). Mass spectrum (ESI, m/z): Calcd. for C26H34N8O2Si, 519.2, found 519.1
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH2:10][CH2:11][NH2:12])[CH:8]=[CH:9][C:3]=2[O:2]1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]3[C:16](=[O:17])[C:15]4=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]4[C:13]3=[O:18])=[CH:6][C:4]=2[O:5]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc2c(c1)OCO2

Procedure:
Forty-one g of 3,4,-methylenedioxyphenethylamine (0.25 moles) was refluxed with 36 g of phthalic anhydride (0.28 moles) and 65 ml. of acetic acid for 2.5 hours. The mixture was cooled whereupon it solidified. The solid mass was broken up and triturated with water and the solid recovered by filtration. Recrystallization from 300 ml of acetic acid and 125 ml of water gave white crystals of the above-named product, m.p. 139°-140.5°.