Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([CH3:19])[N:10]=1.[CH:20]([NH2:24])([CH2:22][CH3:23])[CH3:21]>C(O)C>[Cl:8][C:9]1[N:14]=[C:13]([NH:24][CH:20]([CH2:22][CH3:23])[CH3:21])[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([CH3:19])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CCC(C)N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Yield: 57.2 %

Procedure:
15 ml of triethylamine are added to a solution of 15.6 g of 2,4-dichloro-5-nitro-6-methylpyrimidine (0.075 mole) in 300 ml of absolute ethanol. With ice cooling, 6.6 g of sec. butylamine (0.09 mole) are added dropwise at 0°-5° C over the course of c. 40 minutes to the dark red solution. After the mixture has been stirred for c. 3/4 hour at this temperature, it is poured into c. 700 ml of ice water and the water is extracted 3 times with ether. The ethereal extracts are dried over magnesium sulphate and evaporated. The resultant red oily substance is crystallised from petroleum ether to yield 10.5 g of 2-chloro-4-sec. butylamino-5-nitro-6-methyl-pyrimidine of m.p. 40°-43° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: ClCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(OCc2ccsc2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A mixture of 2-chloro-5-hydroxypyrimidine (200 mg), 3-chloromethylthiophene (610 mg), potassium carbonate (635 mg) and dimethylformamide (3 ml) is stirred at 50° C. for one hour. After the reaction is complete, to the reaction mixture is added water, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate=20:1→20:3), and evaporated to remove the solvent to give 2-chloro-5-(3-thienylmethoxy)pyrimidine (345 mg) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[C:13]1[C:17]([CH3:18])=[CH:16][S:15][CH:14]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[C:13]1[C:17]([CH3:18])=[CH:16][S:15][CH:14]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(-c2cscc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1-c1cscc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of methyl 3-methoxy-4-(4-methyl-3-thienyl)benzoate obtained in step 1 (2.30 g; 8.77 mmol) in EtOH (70 mL), was added at RT an aqueous solution of sodium hydroxide (5 M; 5.26 mL; 26.31 mmol). The reaction mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under vacuum to give a brown solid. It was taken up in water and the aqueous phase was washed twice with EtOAc. Aqueous phase was acidified with concentrated HCl (2 mL) to pH 2. Then it was concentrated under vacuum until a precipitate was formed (⅓ of volume). The suspension was filtered off and dried under vacuum, affording the title compound as a brown solid (1.81 g, 83% for 2 steps). 1H NMR: (DMSO-d5) δ 13.05 (s, 1H), 7.62-7.59 (m, 2H), 7.40-7.39 (d, J=3.23 Hz, 1H), 7.32-7.29 (d, J=7.48 Hz, 1H), 7.25-7.23 (m, 1H), 3.82 (s, 3H), 2.99 (s, 3H). LC/MS (Method A): 248.8 (M+H)+; 246.9 (M−H)−. HPLC (Method A) Rt 3.99 min (Purity: 97.4%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH2:15][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)([CH2:11]2)[C:9]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]23[CH2:11][CH:12]([CH2:15]2)[C:13](=[O:14])[N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]3=[O:25])=[CH:21][CH:20]=1
Reactant: CCCCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 2.1 g of 3-n-heptyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 100 ml of ethanol are hydrogenated in the presence of 0.1 g of palladium-on-carbon and worked up. After purification by column chromatography on silica gel with the system hexane/ethyl acetate 1:1, the title compound is obtained in the form of wax-like crystals. Melting point 69°-71°. Rf (hexane/ethyl acetate 1:1)=0.25.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH2:27][C:28]([OH:30])=O)=[CH:18]1.[CH3:31][CH:32]1[NH:36][CH2:35][C:34]2([CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[S:33]1>ClCCl>[CH3:31][CH:32]1[N:36]([C:28](=[O:30])[CH2:27][CH2:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([CH3:16])[CH:18]=2)[CH2:35][C:34]2([CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[S:33]1
Reactant: Cn1cc(CCC(=O)O)c2ccccc21
Reactant: CC1NCC2(CCN(C)CC2)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1SC2(CCN(C)CC2)CN1C(=O)CCc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.5 %

Procedure:
To a solution of dicyclohexylcarbodiimide (DCC) (1.3 g, 6.3 mmol) in dichloromethane (50 ml) at room temperature was added 3-(1-methyl-indole-3-yl)propanoic acid (1.18 g, 5.8 mmol) and a solution of 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (1.2 g, 6.4 mmol) in dichloromethane (50 ml). The resulting solution was stirred at room temperature for 48 h. During the reaction a white solid precipitated. After filtration, the solvent was evaporated and the crude product was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 100/10/1) to give the title compound (0.7 g) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.60 (d, J=7.82 Hz, 1H, CHC arom), 7.35-7.2 (m, 2H, 2CHC arom), 7.23 (dt, J=1.06, 7.45 Hz, 1H, CHCH arom), 6.90 (s, 1H, CHNH arom), 5.54, 5.07 (2q, J=6.16 and J=6.25 Hz, 1H, CHCH3), 4.63, 3.68 (2d, J=12.0 and J=11.5 Hz, 1H, CHHNCO), 3.75, 3.74 (2s, 3H, NCH3), 3.32 (d, J=11.5 Hz, 0.6H, CHHNCO), 3.17-3.05 (m, 2.4H), 2.8-2.4 (m), 2.68 [t, J=7.6 Hz, C(O)CH2], 2.28, 2.26 (2s, 3H, NCH3), 2.3-2.2 (m), 2.1-2.0 (m), 2.0-1.8 (m), 1.7-1.4 (m), 1.48, 1.43 (2d, J=6.18 and J=6.26 Hz, 3H, CH3—CH) ppm; 13C NMR (CDCl3, 300 MHz) δ 170.6 (C), 137.1 (C), 126.8 (C), 126.7 (CH), 121.8 (CH), 119.0 (CH), 118.9 (CH), 113.7 (C), 109.4 (CH), 59.0 (C), 57.5, 57.2 (CH), 54.6, 54.2 (CH2), 53.2, 52.9 (CH2), 46.3, 46.2 (CH3), 38.1, 37.4 (CH2), 36.9, 36.6 (CH2), 36.4, 34.7 (CH2), 32.7 (CH3), 25.5, 23.5 (CH3), 21.0, 20.9 (CH2) ppm.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:20]=[C:19]([Cl:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>C(COC)OC>[Cl:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=[C:11]2[CH:20]=1
Reactant: Nc1cc(Cl)c2ccccc2n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccccc32)n1
Reaction time: 0.5 h

Procedure:
4 g of ethyl bromopyruvate were added to a solution of 2 g of 2-amino-4-chloroquinoline [Hardman et al C.S., (1958), p. 614] in 40 ml of dimethoxyethane and the mixture obtained was allowed to stand at room temperature for 30 minutes. The quaternary salt thus precipitated was filtered off, washed with ether and then was dissolved in ethanol. The solution obtained was heated at reflux for 1 hour and then the ethanol was removed under vacuum. The residue was dissolved in chloroform and the solution was washed with dilute sodium carbonate solution and water, was decolorized with charcoal and the solvent was evaporated to leave a white solid. This solid was recrystallized from methanol to obtain fine white needles of ethyl 5-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 169°-170° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:36])=[C:17]([CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:22][C:21]2=[O:35])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:36][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][C:17]=2[CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[O:22][C:21]2=[O:35])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O)c1ccc(CCl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 4-(chloromethyl)benzoyl chloride (2.24 g, 11.9 mmol) in methylene chloride (25 mL) was added to a cold (0° C.) stirred suspension of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (4.0 g, 10.8 mmol) and pyridine (0.96 mL, 11.9 mmol) in methylene chloride (25 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1 N HCl and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with sat'd NaHCO3, water, brine and then dried (MgSO4). Evaporation of the solvent gave the crude product which was recrystallized from methylene chloride/hexanes to afford the title compound as white crystals (4.8 g, 85%): mp 142-144° C.; MS m/e: 523 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Nc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (2270 mg, 10.01 mmol), aniline (3 ml) and DMF (20 ml) was heated at 100° C. under an atmosphere of Nitrogen for 7 h. The mixture was then concentrated in vacuo, and the residue triturated with heptane (30 ml) to give the desired product. 1H NMR (400 MHz, CDCl3) δ=7.11 (d, 1 H, J=9.2 Hz), 7.25-7.29 (m, 3 H), 7.40-7.45 (m, 3 H), 8.35 (d, 1 H, J=2.4 Hz) and 9.45 (brs, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:21]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:8]=[C:7]([I:21])[C:6]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(F)(F)F)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(I)c(OCC(F)(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 96 %

Procedure:
2,4-Di-tert-butyl-1-(2,2,2-trifluoro-ethoxy)-benzene (5.06 g, 17.5 mmol), N-iodosuccinimide (4.74 g, 21 mmol) and p-toluenesulfonic acid monohydrate (1.33 g, 7 mmol) were combined in dichloromethane (50 mL) and heated at 38° C. for 19 h. The reaction was washed with 10% Na2S2O3 solution (2×40 mL). The aqueous was backwashed with dichloromethane (70 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide a yellow oil (6.96 g). The material was purified by flash chromatography using hexane to give 5.85 g (81%) of a light pink oil. 1HNMR (250 MHz, CDCl3): δ 7.67 (d, 1H, J=2.4), 7.37 (d, 1H, J=2.4), 4.45 (q, 2H, J=8.2), 1.40 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:17])[CH:7]([N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)OC(C)(C)C)n1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)OC(C)(C)C)n1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution containing (3-nitro-pyrazol-1-yl)-propionic acid tert-butyl ester (2.30 g, 9.53 mmol) in methanol (100 mL), palladium, 10 wt. % on activated carbon, wet (˜300 mg) was added to the solution. The vial was charged with hydrogen gas (via balloon) and the mixture was stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo to afford (3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (1.87 g, 93%) as a yellow oil which was used in the following step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].[S:24]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([C:28]1[CH:29]=[C:30]([NH:34][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:23])[CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])(=[O:27])[NH2:25]
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.14) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (EI) 491.1 [M]; mp 264° C.
Reaction SMILES: [Na].[C:2](OCC)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.Cl>O.C(O)C>[C:21]([CH:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)[CH2:2][C:3]1[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=1)#[N:22]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: N#CC(Cc1ccncc1)c1ccc(F)cc1

Procedure:
250 ml of dry ethanol were added dropwise to metallic sodium (17.3 g/0.7 mol). Ethyl isonicotinate (75.8 g/0.5 mol) and 4-fluorophenylacetonitrile (67.6 g/0.5 mol) were then added dropwise, and the mixture was subsequently heated under reflux for 15 min. After cooling, 600 ml of distilled water were added to the mixture. When the mixture was acidified to pH 1 using concentrated hydrochloric acid (HCl), the desired compound 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethane precipitated as a yellow precipitate. The precipitate was filtered off, washed with distilled water and dried under reduced pressure over phosphorus pentoxide (P2O5). The yield was 85.0 g (62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3[C:22](=[N:21][CH:20]=[CH:19][N:18]=3)[NH:26][N:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1nccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(-c3n[nH]c4nccnc34)cc2)cc1

Procedure:
To a solution of [4-(benzyloxy)phenyl](3-chloropyrazin-2-yl)methanone (1.23 g) in EtOH (20 mL) was added hydrazine hydrate (0.37 mL) at room temperature, and the mixture was refluxed for 2 h. The mixture was concentrated under reduced pressure. The residue was partitioned between AcOEt/THF (1/1) and saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residual crystals were recrystallized from THF/AcOEt to give the title compound (0.60 g).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[OH-].[Na+].C=O.[C:17](OCC)(=[O:19])C>O>[CH2:7]([C:6]1[CH:10]=[C:1]([O:11][CH3:12])[C:2]([OH:3])=[C:4]([CH2:17][OH:19])[CH:5]=1)[CH:8]=[CH2:9]
Reactant: CCOC(C)=O
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1cc(CO)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 2 liter round bottom flask equipped with nitrogen inlet and magnetic stirrer was dissolved eugenol, 99% (Alfa Aesar) in a solution comprised of 286 g NaOH in 1.2 L water at 0° C. A solution of formaldehyde (828 g, 10.2 mol), 37 wt. % solution in water, A.C.S. reagent (Sigma-Aldrich) was added dropwise to the stirring solution. The mixture was stirred under nitrogen at ambient temperature for 4 hours and then 55° C. for 20 h. The reaction mixture was poured into 1 L ethyl acetate and washed with 1 N HCl and deionized water. The crude product containing ˜30 mol % unreacted eugenol was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:10][CH2:11][OH:12].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][CH2:11][OH:12]
Reactant: OCCI
Reactant: CNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCO)c1ccccc1
Yield: 60 %

Procedure:
N-methylaniline (5 mls, 0.05 mol) was reacted with 2-Iodoethanol (3.599 mls, 0.05 mol) and diisopropylethylamine (8.039 mls, 0.05 mol) in ACN at 70° C. for 16 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound as a yellow orange oil, 2a (4.48 g, 0.03 mol, 64.5% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.27-7.15 (m, 2H), 6.81-6.67 (m, 3H), 3.74 (t, J=5.8 Hz, 2H), 3.42 (t, J=5.8 Hz, 2H), 2.92 (s, 3H).
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:36]([F:40])([F:39])([F:38])[F:37]>C(OCC)C>[F:37][B-:36]([F:40])([F:39])[F:38].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=1[S+:3]([CH2:2][F:1])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)CF)cc1
Reactant: Cc1ccc(C)cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2cc(C)ccc2C)cc1

Procedure:
1-((fluoromethyl)sulfinyl)-4-methylbenzene (535 mg, 3.38 mmol) of example 5 was dissolved in dry diethyl ether (15 mL) under an argon atmosphere. P-xylene (0.42 mL, 1.0 eq) was added to the previous solution. The mixture was cooled to a temperature below −50° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.52 mL, 0.92 eq) was added slowly maintaining the same temperature. The mixture was stirred, at the same temperature, until the reaction was complete. HBF4 in diethyl ether solution (54%, 1.29 mL, 2.77 eq) was added. The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and washed with diethyl ether at 0° C. The desired product was obtained as a slightly yellow oily solid (2.25 g). after heating at room temperature
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][S:4][C:3]=1[C:11]([NH:13][CH2:14][C:15]1[CH2:20][C@@H:19]([N+:21]([O-])=O)[C@H:18]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[CH2:17][CH:16]=1)=[O:12]>[Zn].CO.C(O)(=O)C>[NH2:21][C@@H:19]1[CH2:20][C:15]([CH2:14][NH:13][C:11]([C:3]2[S:4][CH:5]=[C:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:2]=2[Cl:1])=[O:12])=[CH:16][CH2:17][C@H:18]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31]
Reactant: CS(=O)(=O)c1csc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)c1Cl
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1csc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)c1Cl
Yield: 65.7 %

Procedure:
To a solution of Example 12D (40 mg, 0.077 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (50 mg, 0.77 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure, and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (25 mg, 66%). 1H NMR (400 MHz, methanol-d4) δ ppm 8.45 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.35-7.47 (m, 2H), 5.82 (m, 1H), 3.82-4.06 (m, 3H), 3.49-3.61 (m, 1H), 3.18 (s, 3H), 2.43-2.62 (m, 2H), 2.24-2.42 (m, 2H). MS (ESI) m/z 493 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[N:8][CH:9]=1)=[O:4].[CH2:11]=[O:12].ClCCl>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:10])[C:7]([CH2:11][OH:12])=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1C
Reactant: C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnc(CO)n1C
Temperature: 135 °C
Yield: 56 %

Procedure:
A suspension of 3-methyl-3H-imidazole-4-carboxylic acid methyl ester (4.0 g, 29 mmol) and paraformaldehyde (18 g, corresponding to 570 mmol) in methanol (40 ml) was heated in a sealed vessel to 135° C. for 60 h. After cooling to ambient temperature, the solution was evaporated to dryness. Flash chromatography (silica, eluent dichloromethane containing 5% methanol) afforded the title compound as white crystals (56% yield). MS: m/e=171(M+H+), mp 145-147° C.
Reaction SMILES: C([N:8]1[CH:13]([CH3:14])[CH2:12][CH:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1COCC1>[CH3:14][CH:13]1[N:8]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH2:12]1
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)C1=CCC(C)N(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(C(=O)OC)=CCC1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of methyl 1-benzyl-6-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate (2.05 g, 8.36 mmol) in THF (15 ml) were added at 0–5° C. allyl chloroformate (1.1 ml, 10.4 mmol). The mixture was immediately raised to room temperature and stirred for 18 hours. After cooled to 0–5° C. a saturated aqueous sodium hydrogen carbonate and ethy acetate were added thereto and the mixture was separated with a separating funnel. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel (55 g) chromatography (hexane/ethyl acetate=6/1→4/1) to give 1-allyl 3-methyl 6-methyl-5,6-dihydro-1,3(2 H)-pyridinedicarboxylate (1.42 g, 71%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.[NH2:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23].[OH-].[Na+]>CO.[Pt]>[CH3:23][CH:22]([CH3:24])[C@H:21]([NH:20][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[CH:17][CH:16]=1)[C:25]([OH:27])=[O:26]
Reactant: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (0.79 g; 3.2 mmol) and L-Valine (0.4 g; 3.4 mmol) are suspended in 15 ml methanol. Then sodium hydroxide is added (0.27 g; 6.72 mmol) and the reaction mixture is stirred at room temperature until a clear solution is obtained. 5% Pt/C (15.8 mg; 2 wt/wt-%) is added. The autoclave is sealed and flushed with argon and hydrogen. The pressure is set to 5 bars and the reaction is stirred at 60° C. The reaction completion is monitored by HPLC. Then the autoclave is flushed with argon and the catalyst is filtered off. Further work-up and crystallisation are done similar to example 1 b2).