Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:30]=[CH:29][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]4[CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[CH:20]=3)[C:15]([OH:17])=O)=[CH:9][CH:8]=2)=[N:4][N:3]=1.N#N.CCN=C=NCCCN(C)C.Cl.[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]4[CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[CH:20]=3)[C:15]([NH:45][C:46]3[S:47][CH:48]=[CH:49][N:50]=3)=[O:17])=[CH:29][CH:30]=2)=[N:4][N:3]=1
Reactant: Nc1nccs1
Reactant: Cc1nnc(-c2ccc(Oc3cc(O[C@@H]4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#N
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(Oc3cc(O[C@@H]4CCN(C)C4=O)cc(C(=O)Nc4nccs4)c3)cc2)o1
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a stirring solution of (R)-(+)-3-[4-(5-Methyl-1,3,4-oxadiazol-2-yl)phenoxy]-5-[(1-methyl-2-oxo-pyrrolidin-3-yl)oxy]benzoic acid (0.2 g) (Intermediate 18) in dry DCM in single necked round bottomed flask fitted with stop cock with N2(g) balloon, N,N′-dimethylamino pyridine (0.060 g) followed by EDCI. HCl (0.23 g) were added at room temperature. After stirring at the same temperature for 15 min, 2-aminothiazole (0.054 g) was added and stirring was continued for 16 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with DCM (20 mL), washed with dil HCl (5 mL, 0.05 N), saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude brown solid (0.080 g). The crude brown solid was purified by solvent trituration.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:14]2)[N:3]=1.[H-].[Na+].[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=2[F:32])[C:9](=[O:12])[O:10][CH3:11])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:14]2)[N:3]=1
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N(Cc1ccccc1F)c1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
47 mg (0.12 mmol) of the compound from example 15A were initially charged in 3 ml of THF, and the mixture was cooled to 0° C. Subsequently, 5 mg (0.12 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at 0° C. for a further 30 min. Thereafter, 14 μl (0.12 mmol) of 2-fluorobenzyl bromide were added dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (acetonitrile:water (+0.1% formic acid) gradient). The crude product obtained in this manner was purified by means of preparative thin-layer chromatography (mobile phase: dichloromethane-methanol 20:1). This gave 8 mg of the target compound (13% of theory).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:21]1([C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCOCCOCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To tetraethylene glycol (213.65 g, 1.1 mol) and triethylamine (20.24 g, 27.8 ml, 200 mmol) in dry dichloromethane (1500 ml) was added dropwise triphenylmethyl chloride (27.88 g, 100 mmol) in dry dichloromethane (500 ml). This solution was left to stir under argon at room temperature for 24 hours. After 24 hours, the reaction was concentrated in vacuo to give a mixture of product and starting material as a yellow oil. This oil was then re-dissolved in dichloromethane (1000 ml), partitioned with sat. aq. NaHCO3 (500 ml), water (3×400 ml) and finally sat. aq. NaCl (500 ml). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated in vacuo to give the title compound as a yellow oil (42.2 g, 95%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.S(=O)(=O)(O)[OH:13]>>[OH:13][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1]
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: O=S(=O)(O)O
Product: CC1=CCC(O)(C(C)(C)O)CC1
Reaction time: 20 h

Procedure:
A mixture of 26.0 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene and 250 ml of 1% sulfuric acid was stirred magnetically for 20 hours, then extracted with four 100 ml portions of methylene chloride. The combined methylene chloride extracts were washed, dried, concentrated and Claisen-distilled to give 22.4 g of the desired product, b.p. 78°-81° C. (0.15 mm).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Cl:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH:14]2[CH2:19][CH:18]([C:20](OCC)=[O:21])[C:17](=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[CH2:15][CH2:16][C:17]3[N:7]=[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]4=[C:20]([OH:21])[C:18]=3[CH2:19]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1CC(Cc2ccc(Cl)cc2)CCC1=O
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ncc2nc3c(c(O)c21)CC(Cc1ccc(Cl)cc1)CC3
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A solution of 1-methyl-1H-pyrazol-4-amine ((J. Catalan et al., J. Heterocycl. Chem., 1985, 22, 997), 200 mg, 2.06 mmol), ethyl 5-(4-chlorobenzyl)-2-oxocyclohexanecarboxylate (EXAMPLE 69, step 3, 1.43 g, 4.85 mmol), and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) in toluene (15 ml) was stirred at 120° C. for 2.5 h. After cooling to room temperature, the solvent was removed in vacuo. The residue (ca. 1.5 g) was dissolved in diphenyl ether (10 ml) and heated at 240° C. for 1 h. After cooling to room temperature, the formed solid was collected by filtration, and washed with diisopropyl ether to give 231 mg (34%) of 7-(4-chlorobenzyl)-1-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-b]quinolin-9-ol. 105 mg of this compound was treated with methanolic hydrochloric acid (5 ml) and the mixture was evaporated. The obtained solid was recrystallized from methanol/diisopropyl ether to give 100 mg of the title compound as a gray crystal.
Reaction SMILES: C([Mg:3][Br:4])C.[C:5]1(=[O:12])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)C>[C:5]1(=[O:12])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:4][Mg:3]
Reactant: CC[Mg]Br
Agent: O=C1CCCCCN1
Solvent: CCOCC
Product: [Mg]Br

Procedure:
At the same time a solution of bromomagnesium caprolactam was prepared from a mixture of 20.6 mL of ethyl magnesium bromide, 2.0 molar in ethyl ether, and 104.74 q of caprolactam.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[CH2:21]([Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])Cl)[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:21][CH3:22])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)c1cc(Br)ncc1F
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (25.3 g, 250 mmol) in 370 ml THF was cooled with a dry-ice acetone bath at −75° C. BuLi (100 ml, 250 mmol, 2.5 M in hexanes) was added dropwise while maintaining the temperature below −50° C. After the temperature of the mixture had reached −75° C. again, a solution of 2-bromo-5-fluoropyridine (36.7 g, 208 mmol) in 45 ml THF was added dropwise. The mixture was stirred for 1 h at −75° C. Triethylchlorosilane (39.2 g, 260 mmol) was added quickly. The temperature stayed below −50° C. The cooling bath was removed and the reaction mixture was allowed to warm to −15° C., poured onto aq. NH4Cl (10%). TBME was added and the layers were separated. The organic layer was washed with brine, dried with MgSO4.H2O, filtered and evaporated to give a brown liquid which was distilled at 0.5 mm Hg to yield the title compound as a slightly yellow liquid (b.p. 105-111° C.). HPLC: RtH11=2.284 min; ESIMS: 290, 292 [(M+H)+, 1Br]; 1H-NMR (400 MHz, CDCl3): 8.14 (s, 1H), 7.40 (d, 1H), 1.00-0.82 (m, 15H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH:4]=[C:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.[Pd]>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[C:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A suspension of 3.88 g of benzyl 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate in 140 ml of ethanol was treated with 0.78 g of 10 percent palladium/carbon, whereupon the mixture was hydrogenated for 16 hours. The reaction mixture was diluted with 1400 ml of water and treated with 4.18 g of sodium carbonate. The catalyst was filtered off and the filtrate was acidified with 25 percent hydrochloric acid. The separated crystals were filtered off under suction, washed with water and dried in a vacuum. There was obtained 2.85 g of 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole -1-carboxylic acid as white crystals with a m.p. of 295° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2OCC[O:28]2)[CH:22]=1.C1(C)C=CC=CC=1.CCOC(C)=O>CC(O)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C3OCCO3)c2)c1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 5 (Example 8, 1.14 g, 2.6 mmol) was suspended in aqueous AcOH (10 mL, 1.5 M in H2O). Glacial AcOH was added dropwise until a clear solution was obtained. The reaction mixture was stirred at room temperature overnight. Evaporation of the solvent under reduced pressure to give a residue. Toluene and EtOAc were added and the mixture was concentrated again to give the crude product that could be purified by silica gel chromatography (hexanes/EtOAc: 1/4). The desired 3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 6 was obtained as a yellow foamy solid (0.91 g, 89%). MS m/z 389.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ0.61 (m, 2 H), 0.85 (dd, J1=6.9 Hz, J2=12.4 Hz, 2 H), 2.25 (s, 3 H), 2.87 (m, 1 H), 5.95 (brs, 2 H), 6.57 (brs, 1 H), 7.44 (d, J=8.0 Hz, 1 H), 7.67-7.78 (m, 4 H), 8.07 (s, 1 H), 8.09 (d, J=1.3 Hz, 1 H), 8.31 (s, 1H), 10.12 (s, 1 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]=[O:14].Cl>CS(C)=O.C[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Methyl 2-(4-chlorophenyl)acetate (36.7 g, 199 mmol) and paraformaldehyde (6.27 g, 209 mmol) were dissolved/suspended in DMSO (400 mL) and treated with NaOMe (537 mg, 9.94 mmol). The mixture was allowed to stir at room temperature for 2 hours to completion by TLC analysis of the crude. The reaction was poured into ice-cold water (700 mL; white emulsion) and neutralized with the addition of 1M HCl solution. The aqueous layer was extracted with ethyl acetate (3×), and the organics were combined. The organic layer was washed with water (2×), brine (1×), separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. The residue was loaded onto a large fitted filtered with silica gel and eluted with 9:1 hexanes:ethyl acetate until the starting material/olefin were collected. The plug was then eluted with 1:1 hexanes:ethyl acetate until the pure desired product was eluted completely. The concentrated pure fractions yielded methyl 2-(4-chlorophenyl)-3-hydroxypropanoate as a colorless oil (39.4 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](OC(ON=C(C#N)C(N)=O)=O)=[CH:35][CH:34]=1)([O-:32])=[O:31].O>O1CCCC1>[N+:30]([C:33]1[CH:38]=[CH:37][C:36]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: N#CC(=NOC(=O)Oc1ccc([N+](=O)[O-])cc1)C(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenyl alanine (0.6 g) and triethylamine (0.28 ml) in dry tetrahydrofuran (12 ml), 2-p-nitrophenyloxycarbonyloxyimino-2-cyanoacetic acid amide (0.6 g) is added, and the resulting mixture is stirred at room temperature for 1.5 hours. The reaction mixture is admixed with water and extracted with ethyl acetate. The organic layer is washed with an aqueous solution of sodium chloride, dried and concentrated. The residue is recrystallized from an ethanol-petroleum ether mixture to give N-benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (0.5 g) as crystals.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2N)[O:7][CH2:6]1)[CH2:2][CH3:3].FC(F)(F)C(O)=O.[N:26]([O-:28])=[O:27].[Na+].C(=O)([O-])[O-].[Ca+2]>O.S([O-])([O-])(=O)=O.[Cu+2].[Cu-]=O>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:26]([O-:28])=[O:27])[O:7][CH2:6]1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)C1COc2cccc(N)c2C1
Reactant: O=N[O-]
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCN(CCC)C1COc2cccc([N+](=O)[O-])c2C1
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-aminochroman (Example 14; 0.050 g, 0.20 mmol) was dissolved in a mixture of trifluoracetic acid (0.080 ml, 1.0 mmol) in water (5 ml). The clear solution was cooled to 0°-4° C. Sodium nitrite (0.017 g, 2.5 mmol) in water (1.0 ml), was added dropwise with good stirring. The solution was stirred for 15 minutes and neutralized with calcium carbonate. A solution of sodium nitrite (0.50 g, 7.2 mmol) in water (1.0 ml) was added followed by a mixture of copper sulfate (0.10 g, 0.62 mmol) and copper (1) oxide in water (1.0 ml). The solution was stirred at 0° C. for 20 minutes and then at ambient temperature for 2 hours. The solution was extracted with diethyl ether. The organic phase was dried with sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel by elution with ethyl acetate/hexane 1:9 to give the title compound. Mp 150°-151° C. (hydrochloride).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)C=CC=CC=1.[C:39]([C:41]1[NH:45][C:44]([CH2:46][CH2:47][CH3:48])=[N:43][C:42]=1[N:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](=[O:59])[C:55]([F:58])([F:57])[F:56])#[N:40].CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[C:39]([C:41]1[N:45]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[NH:8][N:9]=[N:10][N:11]=3)=[CH:20][CH:21]=2)[C:44]([CH2:46][CH2:47][CH3:48])=[N:43][C:42]=1[N:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](=[O:59])[C:55]([F:58])([F:56])[F:57])#[N:40]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 26, 2.1 g), 5-cyano-4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2-propylimidazole (Example 18, 0.89 g), N,N-dimethylformamide (10 mL), and anhydrous K2CO3 (0.5 g) were stirred at room temperature under nitrogen atmosphere for 24 hours. Ethyl acetate (50 mL) was added and inorganic solids were removed by filtration. The filtrate was evaporated at reduced pressure and the major product was isolated by flash chromatography on silica gel (toluene acetonitrile 96:4) to afford the title compound in its triphenylmethyl-protected form (1.3 g). This material was dissolved in methanol (50 mL), treated with aqueous 10% citric acid (1.5 mL) and heated at reflux for 90 minutes. After cooling to room temperature, water (10 mL) and hexanes (100 mL) were added and the mixture was shaken vigorously. The methanol layer was separated, washed again with hexanes and evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The resulting gum was dissolved in ether, concentrated and allowed to stand overnight to give some seed crystals. The remaining gum was dissolved in tertbutyl methyl ether, seeded and diluted with diisopropyl ether. Crystallization gave the title product after filtration. MS (CI, CH4 +NH3) 531 (m+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:46]([C:49]1[S:50][CH:51]=[C:52]([C:54](O)=[O:55])[N:53]=1)[CH2:47][CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:54]([C:52]3[N:53]=[C:49]([CH2:46][CH2:47][CH3:48])[S:50][CH:51]=3)=[O:55])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Reactant: CCCc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.24 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.14 g), 2-propylthiazole-4-carboxylic acid (example 87, step c) (0.084 g) and triethylamine (0.27 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.14 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:9]Cl>>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][N:5]=1
Reactant: ClCl
Reactant: N#Cc1cccnc1
Product: N#Cc1ccc(Cl)nc1

Procedure:
passing a vaporized feed stream including 3-cyanopyridine, chlorine and an inert gas into a first reaction zone having a hot spot at a temperature of about 350° C. to about 420° C., and subsequently passing the stream through a second reaction zone having a temperature of about 200° C. to about 340° C., so as to produce 2-chloro-5-cyanopyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: CCOC(=O)c1sc(NC(=O)c2cc(Cl)ccc2O)nc1-c1ccccc1
Yield: 69.4 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]([CH3:24])[NH:5]1)#[N:2].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1.N1C=CC=CC=1>[C:1]([N:3]=[C:4]1[NH:5][C:6]([CH3:24])=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(=NC#N)NC1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC(=NC#N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 13 h
Yield: 84.7 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-2-cyanoimino-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (565 mg, 1.72 mmoles) in dry tetrahydrofuran (70 ml) and pyridine (2.0 ml) was cooled to 0° C. and treated with ethyl chloroformate (0.17 ml, 2.24 mmoles) dropwise under argon. After the addition was completed, the cooling bath was removed and the reaction was allowed to stir at room temperature for 13 hours. Dry dimethylformamide (2.0 ml) was added and the reaction suspension became a homogeneous solution. It was then treated with triethylamine (0.5 ml) followed by ethyl chloroformate (0.1 ml). The reaction was allowed to stir at room temperature for 1 hour and then diluted with ethyl acetate. It was washed with 1N hydrochloric acid, water, sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (10% ethyl acetate in dichloromethane) to provide a light yellow foam (585 mg). This material was combined with another batch of the same product and was crystallized from isopropyl ether-dichloromethane to yield the title compound, melting point 173.5°-175° C.