Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:66]1([CH2:72][SH:73])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]([S:73][C:2]1[C:3]([F:14])=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C1CCCN1c1cccc(Br)c1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CCCN1c1cccc(SCc2ccccc2)c1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Intermediate 98 (1.48 g, 5.73 mmol) in dioxane (50 ml) was stirred under argon. DIPEA (2 ml, 11.47 mmol), xantphos (0.2 g, 0.34 mmol) and Pd2(dba)3 (0.157 g, 0.17 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.64 ml, 5.45 mmol) was slowly added and the reaction stirred for 1 h. The reaction was quenched by the addition of 50 ml of H2O. After extraction with ethyl acetate (three times) the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].Cl.Cl[CH:13](OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15].[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5]/[N:6]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NNCc1ccccc1F
Reactant: CCOC(=O)C(Cl)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)/C=N/NCc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Fluorobenzyl)hydrazine (1.00 g, 7.14 mmol) is suspended in water (3 ml), and the mixture is brought to pH 4 with 4N hydrochloric acid. It is then cooled in an ice bath, and a solution of ethyl chloro(ethoxy)acetate (1.37 g, 8.21 mmol) in dioxane (10 ml) is added. The mixture is stirred at RT for 1 h, then made weakly alkaline (pH 8) with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate. The crude product is purified by chromatography on silica gel (eluent: dichloromethane with increasing methanol content). 1.40 g (88% of theory) of the desired compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[OH:26])=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
6-Chloro-5-(4-chloro-phenyl)-nicotinic acid (1.4 g, 5 mmol) was dissolved in N,N-dimethylformamide (30 mL). To this solution was added sequentially (1R,2R)-2-amino-cyclohexanol hydrochloride (0.87 g, 6 mmol), TBTU (1.84 g, 6 mmol), and N-ethyldiisopropylamine (4.47 mL, 26 mmol). The reaction mixture was stirred at room temperature for 72 hours then concentrated in vacuo. The residue was then dissolved in ethyl acetate (100 mL) and washed with 0.5 N HCl (100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The aqueous phases were extracted with ethyl acetate (2×100 mL), the organics were combined and the whole was dried over MgSO4 and concentrated in vacuo. The solid residue was purified by stirring with (ethylacetate/heptane 1:2, 50 mL) to give 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as a colorless solid, 1.4 g (73% yield). m/z (ISP+): 364.9, 366.9 (M+H).
Reaction SMILES: I[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:29]([OH:32])[C:30]#[CH:31]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:31]#[C:30][CH2:29][OH:32])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: C#CCO
Reactant: Ic1cccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of N-(4-(3-iodopyridin-2-yloxy)phenyl)pyridin-2-amine (0.300 g, 0.771 mmol), copper(I) iodide (3.91 μL, 0.116 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.034 g, 0.048 mmol), triethylamine (0.800 mL, 5.74 mmol) and propargyl alcohol (0.150 mL, 2.54 mmol) in THF (5 mL) was stirred at rt under an atmosphere of argon for 3.5 h. The reaction was evaporated onto silica gel and purified by flash chromatography (Isco, (60 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97). The material was stirred over MeOH, filtered and dried in vacuo to give a white crystalline solid. MS (ESI, pos. ion) m/z: 318.0. IC50 (uM)=0.2612.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccnc2)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (38 mg, 0.072 mmol, Intermediate B), imidazole (7 mg, 0.11 mmol, Aldrich, St. Louis, Mo.) and cesium carbonate (46 mg, 0.14 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×40 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white glass. The crude product was purified by silica gel chromatography, eluting with 5% MeOH in EtOAc to give 2-(4-((S)-2-((1H-imidazol-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (28 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1n[nH]c2cc(Cl)c(C#Cc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]c2cc(Cl)c(C#Cc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
A solution of methyl 6-chloro-5-(phenylethynyl)-1H-indazole-3-carboxylate (20 mg, 0.064 mmol) in methanol (1 mL) was treated with 10N aqueous sodium hydroxide (2 drops) and stirred at room temperature for 16 hours. The reaction mixture was then treated with additional 10N aqueous sodium hydroxide (2 drops) and heated to 70° C. for two hours. The cooled reaction mixture was evaporated in vacuo, and treated with 1N citric acid. The resulting solids were collected by filtration, dried and purified using prep-HPLC to afford the title compound (1 mg). MS (ES+) 374.9 (M+DMSO)+. Retention time: 1.8 min; Xbridge C18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:20][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(Br)ccc1Oc1ccccc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(Br)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 124b (412 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (206 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.73 (s, 3H) 6.69 (d, J=7.35 Hz, 2H) 6.96 (d, J=7.72 Hz, 2H) 7.05-7.15 (m, 3H) 7.24-7.36 (m, 2H) 7.68 (dd, J=8.82, 2.57 Hz, 1H) 7.75 (d, J=8.46 Hz, 1H) 7.82 (d, J=2.21 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 8.86 (d, J=8.82 Hz, 1H) 10.93 (s, 1H) 14.49 (s, 1H); MS (ESI+) m/z 408 (M+H−TFA)+.
Reaction SMILES: Br.Br.[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1.CCN(CC)CC.Cl[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35]>C(Cl)Cl>[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][N:22]([CH2:33][C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1
Reactant: CC1CCN(c2nc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(CC(=O)N4CCOCC4)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
A solution of 4-methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl dihydrobromide (as prepared in Example 67, step (c), 0.10 g, 0.21 mmol) in CH2Cl2 (5 mL) was treated with Et3N (0.10 mL, 0.75 mmol) and 2-chloro-1-morpholin-4-yl-ethanone (as prepared in the previous step, 39 mg, 0.24 mmol). The reaction stirred at room temperature for 18.5 h. The reaction was diluted with CH2Cl2 and washed with water. The aqueous layer was further extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.11 g, 117%, some salt remains) as a yellow solid, which was used directly in the next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 1H, J=9.2 Hz), 6.02 (d, 1H, J=9.2 Hz), 3.76-3.67 (m, 8H), 3.26 (br s, 2H), 3.14-3.07 (m, 2H), 3.03-2.93 (m, 2H), 2.63 (br s, 4H), 1.74-1.65 (m, 2H), 1.65-1.58 (m, 1H), 1.45-1.39 (m, 3H), 1.37-1.24 (m, 3H), 0.97 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C21H32N6O4, 433.2 (M+H), found 433.1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cccnc3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 92.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(2-methylpyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.05 g, 0.08 mmol) prepared in Example 70c, triethylsilane (0.06 mL), trifluoroacetic acid (0.08 mL) and dichloromethane (0.75 mL), to yield the title compound (34 mg, 98%) as a colorless solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][NH:23][CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][N:23]([C:2]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:9])[CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:12][CH2:13]1
Reactant: c1cnc2c(c1)N(CC1CC1)CCC1CNCCN21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCN2c3ncccc3N(CC3CC3)CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nicotinoyl chloride hydrochloride (58.2 mg, 0.317 mmol) was added at room temperature to a solution of the product of Example 74A (82 mg, 0.317 mmol) in CH2Cl2 (4 mL) and triethylamine (0.111 mL, 0.793 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 Maqueous (NH4)2CO3-methanol, 40:60-0:100 over 15 minutes) to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.16-0.21 (m, 2H), 0.45-0.54 (m, 2H), 0.93-1.03 (m, 1H), 1.61-1.75 (m, 1H), 1.79-1.91 (m, 1H), 2.90-3.05 (m, 2H), 3.19-3.30 (m, 2H), 3.34-3.50 (m, 4H), 3.54-3.64 (m, 1H), 3.71-3.92 (m, 2H), 6.74 (dd, J=7.8, 4.7 Hz, 1H), 7.00 (dd, J=7.9, 1.5 Hz, 1H), 7.45 (ddd, J=7.9, 4.9, 0.9 Hz, 1H), 7.65 (dd, J=4.6, 1.5 Hz, 1H), 7.83 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.58-8.67 (m, 2H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].CO[C:12](OC)([CH3:15])[CH:13]=O>>[CH3:13][C:12](=[N:5][NH:6][C:7](=[NH:8])[NH2:9])[CH:15]=[N:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: COC(C)(C=O)OC
Reactant: N=C(N)NN
Agent: O=C(O)O
Product: CC(C=NNC(=N)N)=NNC(=N)N

Procedure:
reacting the filtered aminoguanidine bicarbonate with methylglyoxal dimethyl acetal in an aqueous reaction medium to produce 2,2'-(methyl-1,2-ethanediylidene)bis[hydrazine carboximidamide]; and
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=1>C(#N)C.O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:14]([CH3:15])[CH3:16])[C:9]([OH:13])=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Solvent: CC#N
Solvent: O
Product: Cc1c(Cl)cc(C(C)C)c(O)c1[N+](=O)[O-]
Reaction time: 0.83 h
Yield: 81.9 %

Procedure:
Acetyl nitrate obtained by mixing acetyl anhydride (1.12 g, 11 mmol) with fuming nitric acid (693 mg, 11 mmol) at 0° C. was dropped into a solution of 4-chloro-2-isopropyl-5-methylphenol (1.84 g, 10 mmol) in acetonitrile (20 ml) at 0° C. followed by stirring for 50 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (80 g of silica gel; developing solvent, hexane:methylene chloride=30:1→10:1) to provide 1.88 g (yield 83%) of 4-chloro-6-isopropyl-3-methyl-2-nitrophenol as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[Cl:10][C:9]1[CH:8]=[CH:7][C:4](/[CH:5]=[CH:14]/[N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])/C=C/c1ccc(Cl)c(Cl)c1
Yield: 38.4 %

Procedure:
Using analogous conditions and workup as described for the preparation of intermediate I-1a above, 3,4-dichlorobenzaldehyde (10 g, 74.074 mmol) in ethanol (100 mL) was reacted with nitro methane (4.12 mL, 74.074 mmol) and 10N NaOH (2.96 g in 7.4 mL of H2O, 74.074 mmol) to afford 6.2 g of the product (39% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([O:29]CC)=O)[N:10]=2)[CH2:4][CH2:3]1.[NH2:32]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([NH2:32])=[O:29])[N:10]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
Ethyl 2-(trans-4-hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate and the imidazole ester. Ethyl 5-amino-2-(trans-4-hydroxy-cyclohexylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.240 g, 0.598 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.968 g, 5.98 mmol) in dichloromethane (20 mL) were reacted according to general procedure F. A mixture of the title compound and the imidazole ester were formed and were taken on without further purification. MS (ESI) m/z 399 [M+1]+ (title compound), 522 [M+1]+ (imidazole urea).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2].C([N:17]=[C:18]=[N:19]C1C=NC=CC=1)(C)(C)C>>[C:18]([N:19]=[C:5]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[NH:4][CH:1]([CH3:3])[CH3:2])#[N:17]
Reactant: CC(C)N=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CC(C)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-isopropyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-isopropyl-N'-3-pyridylguanidine was obtained with a melting point of 154.5°-155.0° C. Warning: Strongly exothermic reaction was observed in this case.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19]C)=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCn2c1cc(Cl)c2C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1c(Cl)cc2n1CCC2C(=O)O

Procedure:
Methyl 5-benzoyl-6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (1.10 g.) in 30 ml. of methanol containing 2 molar equivalents potassium carbonate in 10 ml. of water is heated at reflux temperature for three hours. The methanol is removed in vacuo and water is added to the residue. The solution is extracted with ethyl acetate, the aqueous phase is cooled to 0° and made acidic with 20% hydrochloric acid. The solid which precipitates is collected by filtration, washed with cold water and dried in vacuo. The residue is crystallized from methanol-water to give 5-benzoyl-6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, m.p. 190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:9])[F:20])[N:16]=2)=[O:18])[CH:7]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)ncn1)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-6-chloropyrimidine (230 mg, 1.78 mmol) in DCM (15 mL) is added 6-(trifluoromethyl)picolinoyl chloride (276 mg, 1.78 mmol) and DIPEA (0.912 ml, 5.33 mmol). The mixture is stirred overnight at RT. The mixture is diluted with DCM (10 mL), washed with saturated NaHCO3 solution (25 mL). The organic layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by prep HPLC E, delivering the title compound as a yellowish solid (102 mg, 19%); LC-MS A: tR=0.89 min; [M+H]+=302.92.
Reaction SMILES: [CH3:1][P:2](=[O:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.O>[CH2:8]([N:15]1[CH2:6][CH2:5][P:2](=[O:7])([CH3:1])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CP(C)(=O)C=C
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CP1(=O)CCN(Cc2ccccc2)CC1
Yield: 70.3 %

Procedure:
A solution of methyl divinyl phosphine oxide (1.16 g, 10.0 mmol) and benzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford 1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white solid (1.57 g, 70% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:17](=[O:27])[CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:20])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[OH:27][C:17]1[C:8]2[C:7](=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:10][CH:9]=2)[N:6]=[C:4]([CH2:3][O:2][CH3:1])[C:18]=1[C:19]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:20]
Reactant: COCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
5.03 g of 4-dimethylamino-pyridine were added to a solution of 16.5 g of the product of Step B in 205 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 41/2 hours. The tetrahydrofuran was distilled off under reduced pressure at 40° C. and the dry residue was taken up in 500 ml of water. 42 ml of N hydrochloric acid were added to the mixture and the suspension was stirred at 20° C. for 30 minutes and was vacuum filtered. The product was washed with water, dried under reduced pressure at 70° C. and was crystallized from 310 ml of dioxane. The mixture was vacuum filtered at 15° C. and the product was washed with 30 ml of dioxane and dried under reduced pressure at 70° C. to obtain 13.3 g of 4-hydroxy-2-methoxymethyl-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 260° C.
Reaction SMILES: [C:1](O)(=O)C.O.[CH:6](=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C=O>[CH2:1]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[O:15]
Reactant: CC(=O)O
Reactant: CCCCCCCCC=O
Agent: C=O
Solvent: O
Product: C=C(C=O)CCCCCCC
Temperature: 50 °C

Procedure:
A 5-liter flask fitted with an overhead stirrer and condenser was charged with di-N-butyl amine (61 g, 0.47 mol) and acetic acid (56 g, 0.9 mol). Roughly 900 ml of 37% formaldehyde solution in water (351 g formaldehyde, 11.7 mol) was then added and the resulting solution was heated to 50° C. with stirring. After this temperature was reached nonanal (1000 g, 7.0 mol) was fed in over about 2 h. A slight exotherm was noticed during the feed. Monitoring by GC showed the consumption of nonanal and the production of 2-methylene nonanal, finally reaching roughly 95% conversion after the addition was complete. The reaction mixture was allowed to cool to room temperature, poured into a separatory funnel, and washed once with 5% HCl solution. The organic layer was then washed once with saturated sodium bicarbonate, then taken directly on to the next step.