Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:37][N:38]([CH3:75])[C:39]1[CH:44]=[CH:43][C:42](/[N:45]=[N:46]/[C:47]2[CH:52]=[CH:51][C:50](/[N:53]=[N:54]/[C:55]3[C:66]4[C:67]5[C:58]([NH:59][CH:60]([C:68]6[CH:73]=[CH:72][C:71](O)=[CH:70][CH:69]=6)[NH:61][C:62]=5[CH:63]=[CH:64][CH:65]=4)=[CH:57][CH:56]=3)=[CH:49][CH:48]=2)=[CH:41][CH:40]=1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:71]2[CH:70]=[CH:69][C:68]([CH:60]3[NH:59][C:58]4[C:67]5[C:66]([C:55](/[N:54]=[N:53]/[C:50]6[CH:51]=[CH:52][C:47](/[N:46]=[N:45]/[C:42]7[CH:41]=[CH:40][C:39]([N:38]([CH3:75])[CH3:37])=[CH:44][CH:43]=7)=[CH:48][CH:49]=6)=[CH:56][CH:57]=4)=[CH:65][CH:64]=[CH:63][C:62]=5[NH:61]3)=[CH:73][CH:72]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CN(C)c1ccc(/N=N/c2ccc(/N=N/c3ccc4c5c(cccc35)NC(c3ccc(O)cc3)N4)cc2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C3Nc4cccc5c(/N=N/c6ccc(/N=N/c7ccc(N(C)C)cc7)cc6)ccc(c45)N3)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To an ice cooled solution of 1.47 g of 4-{[6-(acryloyloxy)hexyl]oxy}benzoic acid (5.00 mM) and 0.24 g of DMAP (2.00 mM) in 20 ml of dichloromethane, was added a solution of 1.03 g of DCC (5.00 mM) in 10 ml of dichloromethane dropwise. After complete addition (within 15 min) stirring was continued at 0° C. for further 90 min., then 2.57 g of 4-{6-[(E)-(4-{(E)-[4-(dimethylamino)phenyl]diazenyl}phenyl)-diazenyl]-2,3-dihydro-1H-perimidin-2-yl}-phenol (5.00 mM) were added to the reaction mixture which is further stirred for 3 h at room temperature. The obtained dark-brown mixture was filtered through a pad of 20 g of celite filter aid, the cake was washed with 60 ml of dichloromethane and the filtrate was concentrated to approximately ⅓, followed by precipitation with cyclohexane/hexane 50 ml/50 ml. The obtained brown precipitate was filtered off, washed with 10 ml of hexane and dried to give 3.80 g (4.80 mM, 96%) of 4-{6-[(E)-(4-{(E)-[4-(dimethylamino)phenyl]diazenyl}phenyl)diazenyl]-2,3-dihydro-1H-perimidin-2-yl}phenyl 4-{[6-(acryloyloxy)hexyl]oxy}benzoate dark-brown powder; λmax=547 nm, ε=53000 (THF). For total purification, the dye might be flash chromatographed on silica gel.
Reaction SMILES: [Cl-:1].[NH4+].O.[CH3:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C@H:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=2)[CH2:8][CH2:7]1.N>C(O)CC>[CH3:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C@H:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=2)[CH2:8][CH2:7]1.[ClH:1]
Reactant: [Cl-]
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: N
Agent: [NH4+]
Solvent: O
Solvent: CCCO
Product: Cl
Temperature: 25 °C

Procedure:
8.75 g of ammonium chloride are dissolved in 100 ml of n-propanol and 35 ml of water at T=50° C. 50 g of free sertraline base dissolved in 100 ml of n-propanol are added dropwise to the solution thus obtained. It Is heated under reflux and is maintained under agitation under a light nitrogen flow until ammonia is no longer evolved and the pH of the solution becomes slightly acidic. It is cooled to room temperature and is seed crystallized with 0.5 g of sertraline hydrochloride form II. A crystalline solid begins to precipitate and agitation is maintained for 1.5 hours. The solid is filtered, washed and dried under vacuum. 49.3 g of sertraline hydrochloride form II (yield 88%) are obtained.
Reaction SMILES: C.CC.[CH3:4]CC.[CH3:7][CH2:8]CC.[CH2:11]([S:19]([OH:22])(=[O:21])=[O:20])[CH2:12][CH2:13][CH2:14]CCCC>CCCCCC>[CH4:4].[CH3:7][CH3:8].[CH3:11][CH2:12][CH3:13].[CH2:11]([S:19]([OH:22])(=[O:21])=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCS(=O)(=O)O
Reactant: CCCC
Agent: C
Agent: CC
Solvent: CCC
Solvent: CCCCCC
Product: CCCCS(=O)(=O)O

Procedure:
In a Gotte foam beater (DIN 53 902, Part 1), methane, ethane, propane, butane, n-hexane and n-octane sulfonic acid were tested for their foaming behavior in 0.5% aqueous solution (0° Gh) at 40° C. The solutions of methane, ethane, propane and butane sulfonic acid did not produce any foam.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][N:15]([CH3:17])[CH:16]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Cc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCC(=O)C(=CN(C)C)c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 1-phenylbutan-2-one (5.00 g, 33.7 mmol) in DMF (80.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (6.03 g, 50.6 mmol). The resulting mixture was stirred at 90° C. for 16 h. Upon completion, the reaction mixture was quenched with water (40.0 mL), extracted with EtOAc (4×50.0 mL), and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give a brown oil. This brown oil was purified by flash chromatography to give the title compound as a yellow oil (3.32 g). 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.32 Hz, 3H), 2.19 (q, J=7.49 Hz, 2H), 2.67 (s, 6H), 7.14-7.41 (m, 5H), 7.61 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]OS([O-])=O.[K+].Cl.C(OC(C)C)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCCC=O)c(C)c1OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)c(OCc2ccccc2)c(CCCC(=O)O)c(C)c1OCc1ccccc1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanal (450 mg, 1.12 mmol) in DMF (11.5 mL) was added Oxone (350 mg, 1.12 mmol) giving a cloudy white solution. The suspension was stirred vigorously overnight and poured over 10 mL 2.5 M HCl and stirred until the solution clarified. Isopropyl acetate (iPrOAc) (25 mL) was added after the exotherm subsided. The organics were washed 2×10 mL 2.5 M HCl, 1×10 mL saturated aqueous NaCl and dried over Na2SO4. Concentration gave 435 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid as a white solid. MS M++H at 419 m/z; 1H NMR (400 MHz, CDCl3) δ=7.50 (m, 4H), 7.43-7.34 (m, 6H), 4.75 (s, 2H), 4.74 (s, 2H), 2.71 (t, 2H), 2.37 (t, 2H), 2.26 (s, 3H), 2.26 (s, 6H), 1.85 (s, 2H) ppm.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[CH:17]=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19]N1C(=O)CCC1=O.O.C(=O)(O)[O-]>CN(C=O)C>[Cl:19][C:8]1[C:9]2[CH:14]=[N:13][C:12]([S:15][CH3:16])=[N:11][C:10]=2[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]=1[CH:17]=[O:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1ncc2cc(C=O)n(C3CCCC3)c2n1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(Cl)c(C=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
Compound 229 (3.10 g, 11.9 mmol) and N-chlorosuccinimide (1.74 g, 13.0 mmol) were dissolved in DMF (30 mL) and stirred at 100° C. After 1 h, the temperature of the reaction was reduced to 65° C. and 0.35 eq of NCS were added. After 30 min, the reaction contents were poured into water (10×) and saturated bicarbonate was added (300 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 7% ethyl acetate in hexanes) afforded 5-chloro-7-cyclopentyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (230) (1.37 g, 39% yield). 1H NMR (500 MHz, CDCl3) δ ppm 10.17 (s, 1 H) 8.91 (s, 1 H) 5.73-5.96 (m, 1 H) 2.63 (s, 3 H) 2.29-2.47 (m, 2 H) 1.97-2.16 (m, 4 H) 1.63-1.83 (m, 2 H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])#[CH:20].C1(C)C=CC=CC=1>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]#[C:20][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C#Cc1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(C#Cc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 32.5 °C
Yield: 84.5 %

Procedure:
6-Chloro-3-nitro-pyridin-2-ylamine (16.2 kg, 93.3 mol), acetonitrile (130.8 L), cuprous iodide (0.18 kg, 1.0 mol), and bis(triphenylphosphine)palladium (II) chloride (0.66 kg, 0.9 mol) are combined under a nitrogen atmosphere at 20-25° C. with stirring. Triethylamine (19.7 L, 141.3 mol) is added and the mixture is heated to 30-35° C. A solution of 1-ethynyl-2,4-difluoro-benzene (18.0 kg, 130.3 mol) in acetonitrile (32.6 L) is added under a nitrogen atmosphere at 30-35° C. The mixture is stirred at 15-25° C. for 2-4 h. Toluene (80.0 L) is added and the mixture is stirred for 0.5-1 h, then cooled to 0-5° C. and stirred for 2-4 h. The reaction mixture is centrifuged and the filter cake is rinsed with toluene (2×64 L) and water (2×32.4 L). The solids are dried under reduced pressure below 50° C. to furnish the title compound as a yellow solid (21.7 kg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15]C3C=CC=C([N+]([O-])=O)C=3)[C:13]([CH2:25][CH2:26]O)=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(OCCC1N(CC2C=CC([N+]([O-])=O)=CC=2)C(SC2C=C(Cl)C=C(Cl)C=2)=C(C(C)C)N=1)(=O)[NH2:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:25][C:26]#[N:32])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CCO)n(Cc2cccc([N+](=O)[O-])c2)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CC#N)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 83 %

Procedure:
2-(2-Carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(m-nitrobenzyl)-1H-i-imidazole (128b) was obtained from (126b) by the same synthetic process as that for (128a) in Example 140 (yield 83%). mp 167-169° C.
Reaction SMILES: [BrH:1].[OH-].[Na+].[OH:4][CH2:5][C@@H:6]1[CH:21]=[C:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:8]([CH3:9])[CH2:7]1.N>Br.CS(C)=O.CS(C)=O>[Br:1][C:13]1[NH:14][C:15]2[C:22]3[C:12]=1[CH2:11][C@@H:10]1[C:20]([C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:21][C@@H:6]([CH2:5][OH:4])[CH2:7][N:8]1[CH3:9]
Reactant: Br
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Dry gaseous hydrogen bromide is introduced into 100 ml of anhydrous dimethylsulfoxide at room temperature. The quantity of the introduced hydrogen bromide gas is measured by titrating with 0.1N sodium hydroxide solution. The hydrogen bromide is introduced until the concentration of the gas reaches 0.0003-0.0005 mole/ml. One g (0.003937 mole) of lysergol is dissolved in an aliquot amount of this hydrogen bromide-dimethylsulfoxide mixture which contains 12 equivalents of hydrogen bromide. After complete dissolution, this mixture is stirred at room temperature for 20 minutes, then poured into a 5-fold volume of ice-water. Thereafter, the solution is made alkaline by adding aqueous ammonia up to a pH value of 8.9, the precipitate is filtered off, washed with water, dried and purified on a Kieselgel column by using an 8:2 mixture of chloroform and methanol to give the named compound in a yield of 0.76 g (0.00228 mole, 58%), m.p.: 193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]Br.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.CO>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1C
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Br)ccc1C
Yield: 17.2 %

Procedure:
To 50 g of Na-X type zeolite dry powder (Zeolum type F-9; 100 meshes or finer, produced by Tosoh Corporation) was added dropwise 7.51 g (50.0 mmol) of methyl 2-methylbenzoate with stirring. Further, 3.9 ml (75 mmol) of bromine was added dropwise thereto at 45˜50° C., and the mixture was stirred at 80° C. for 1 hour. To the reaction mixture was added a solution of potassium carbonate (5.5 g) in water (50 ml) and methanol (250 ml). The mixture was stirred at room temperature for 10 minutes and filtered. The residual zeolite powder was washed with warmed hydrous methanol (10%, 250 ml). The filtrate and the washing were combined and concentrated. The residue was diluted with ethyl acetate, washed twice with water, dried and concentrated. The residue (2.98 g) was subjected to silica gel column chromatography (eluted with n-hexane:toluene=10:1 and then 5:1 and then 3:1) to obtain 1.97 g (8.60 mmol) of methyl 5-bromo-2-methylbenzoate as crystals.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])=[CH:4][S:3]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[O:1]=[C:2]1[S:6][C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])=[CH:4][S:3]1
Reactant: CCOC(=O)C(=NOC)c1csc(=O)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)O)c1csc(=O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a solution of thus obtained ethyl 2-(2-oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetate (anti isomer, 1.7 g.) in ethanol (20 ml.) was added dropwise a solution of sodium carbonate 10 hydrate (2.2 g.) in water (10 ml.) and the mixture was stirred at room temperature for 3 hours. After removing ethanol from the resultant solution in vacuo, the residue was acidified with hydrochloric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to give oily product. The oil was allowed to stand in a refrigerator to give 2-(2-oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetic acid (anti isomer, 0.75 g.).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([CH3:23])[C:7](=[O:22])[CH2:8][NH:9][C:10]([CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][C:10]([N:9]([CH2:8][C:7](=[O:22])[CH:6]([CH3:5])[CH3:23])[C:1](=[O:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:11]
Reactant: CC(C)C(=O)CNC(C)(C)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CC(=O)C(C)C)C(C)(C)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
Acetyl chloride (0.24 mL, 3.4 mmol) was added to an ice-cooled solution of 3-methyl-1-[1-methyl-1-(3-nitro-phenyl)-ethylamino]-butan-2-one (600 mg, 2.27 mmol) and triethylamine (0.79 mL, 5.6 mmol) in DCM (10 mL). The mixture was maintained between 0 and 5° C. for 30 min. then concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with water then brine and dried over sodium sulfate. Concentration afforded N-[1-methyl-1-(3-nitro-phenyl)-ethyl]-N-(3-methyl-2-oxo-butyl)-acetamide (620 mg, 89%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:21][S:22]([O:10][C:5]1[CH:6]=[C:7]([CH2:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(O)c([N+](=O)[O-])cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(OS(C)(=O)=O)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h

Procedure:
150 mg of 4-chloro-5-ethyl-2-nitrophenol was dissolved in 1.5 ml of dichloromethane, and 156 μl of triethylamine and 69 μl of methanesulfonylchloride were added at room temperature and stirred for 30 minutes. To the reaction mixture was added 50 ml of water, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 200.7 mg of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH:10]=[CH:11][C:12]1[CH:13]=[N:14][C:15]([C:18](=[O:21])[NH:19][CH3:20])=N[CH:17]=1)C1C=CC=CC=1.[CH2:23](O)C>[Pd]>[CH3:20][NH:19][C:18]([C:15]1[CH:23]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([OH:8])=[O:22])=[CH:13][N:14]=1)=[O:21]
Reactant: CCO
Reactant: CNC(=O)c1ncc(C=CC(=O)OCc2ccccc2)cn1
Agent: [Pd]
Product: CNC(=O)c1ccc(CCC(=O)O)cn1

Procedure:
3-(2-methylcarbamoyl-pyrimidin 5-yl)acrylic acid benzyl ester in ethanol (20 mL) in presence of 15 mg of Pd/C, 10%, and stirred under hydrogen balloon overnight to give 3-(2-methylcarbamoyl-pyridine-5-yl)-propionic acid which was used without further purification.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>C(#N)C>[CH2:1]([N:9]1[CH2:10][CH:11]=[CH:12][CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: C1=CCN(Cc2ccccc2)CC1
Temperature: 71 °C

Procedure:
2.4 mL of benzyl bromide (20 mmol) was added dropwise over an hour to a solution of 1.6 mL of pyridine in 5 mL of acetonitrile. Then reaction mixture was heated at 70 to 72° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in 16 mL of ethanol. 1.1 g of sodium borohydride (30 mmol) was added in small portions over 30 minutes. After stirring for 24 hs reaction mixture was carefully quenched with 50 mL of water and solvents were removed in vacuo. The residue was portioned between ethyl acetate and 2M NaOH solution. Organic extracts were washed with brine, dried over MgSO4 and evaporated to afford crude 3.36 g of crude 1-benzyl-1,2,3,6-tetrahydropyridine which was used in the next step without purification.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].IC.[C:16](=O)([O-])[O-].[K+].[K+].C([N+](CC)(CC)CC1C=CC=CC=1)C>C(#N)C>[CH3:16][O:1]/[N:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccccc1C=NO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CO/N=C/c1ccccc1CC(=O)O
Reaction time: 8 h

Procedure:
1.8 g (10 mmoles) of 2-hydroxyiminomethyl-phenylacetic acid are reacted with 1.50 ml of iodomethane, 5 g of potassium carbonate and 10 mg of triethylbenzylammonium (TEBA) chloride in 20 ml of anhydrous acetonitrile. The system is left for 6 hours at +80° C. and overnight at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccn(-c2cccnc2)n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl

Procedure:
In step d of Scheme 1, compound (5b) is nitrated with nitric acid (HNO3), preferably in the presence of sulfuric acid (H2SO4) to yield 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (5c). The nitration may be conducted at temperatures from about −10° C. to about 30° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][N:13]2[N:12]=1)=[O:10].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]3[N:12]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:20]=[C:14]3[CH2:15]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(NOC1CCCCO1)c1cc2n(n1)CCCNC2
Reactant: COc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCCn3nc(C(=O)NOC4CCCCO4)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (0.0283 g, 0.101 mmol) and 4-methoxybenzoic acid (0.016 g, 0.105 mmol) in methylene chloride (1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.0434 g, 0.114 mmol) and N-methylmorpholine (0.0333 mL, 0.303 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (2 mL) and washed with aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional methylene chloride (3 mL) and the combined organic layers concentrated to afford Intermediate 30 as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([C:19]2[N:20]=[C:21](O)NC=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:25]1C=CC=C[CH:26]=1.S(Cl)(Cl)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([C:19]2[NH:20][CH:21]=[CH:26][N:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccncc1
Reactant: Oc1nc(-c2ccccc2)c[nH]1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To 177 mg (0.148 mmol) of phenyl hydroxy imidazole (from Step 1) and 50 μL of pyridine in 1.5 mL of methylene chloride at 0° C. was added 32 μL of thionyl chloride, and the resulting brown solution was stirred at room temperature for 2 hour. The reaction mixture was washed with water, dried and concentrated in vacuo. The residue was purified over silica gel to give 105 mg (92%) of conjugated phenyl imidazole biphenyl as an oil which solidified upon standing.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.CN(C=O)C.O>C1COCC1.[Ni]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCCC2)nc1
Reaction time: 2 h
Yield: 96.7 %

Procedure:
5-Nitro-2-(pyrrolidin-1-yl)pyridine (9.52 g, 49.3 mmol) was dissolved in THF (50 mL) and DMF (40 mL) and added to a pressure bottle containing Raney-nickel 2800, water slurry (45%) (9.52 g, 162 mmol). The mixture was stirred for 2 hours at 30 psi under H2 gas. The solution was filtered through a nylon membrane, washed with CH3OH and the filtrate concentrated in vacuo to give the title compound (7.78 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.91 (m, 4H) 3.17-3.29 (m, 4H) 4.30 (s, 2H) 6.25 (d, J=8.7, 1H), 6.90 (dd, J=2.8, 8.7, 1H), 7.55 (d, J=2.6, 1H); MS (ESI) m/z 164 (M+H)+.