Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:24]1([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C)CCCN=C=NCC>CN(C)C=O>[CH:24]1([CH2:30][CH2:31][CH2:32][C:33]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1COC(=O)C1
Reactant: O=C(O)CCCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCC1CCCCC1)C1=C(O)COC1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.0 g (10.0 mmol) of tetronic acid in 30 mL of dry N,N-dimethylformamide at 0° C. is added 1.5 mL (11 mmol) of triethylamine followed by 0.37 g (30 mmol) of 4 dimethylaminopyridine. After stirring at 0° C. for 5 minutes, 2.0 g (11.7 mmol) of 4-cyclohexyl butyric acid is added, followed by 2.25 g (11.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide. After 10 minutes, the ice bath is removed and the reaction mixture is allowed to stir overnight. The reaction mixture is quenched with 1N HCl and the solution is washed three times with hexanes. The combined organic layers are washed with water, dried over magnesium sulfate and evaporated. The residue is flash chromatographed on silica gel using 5% methanol/ethyl acetate with 2 mL of acetic acid/liter to give an orange solid: m.p. 38-42° C.; IR (film) 2920, 2840, 1770, 1690, 1660, 1600 cm-1 ; NMR (CDCl3) δ 0.9 (m, 2H), 1.2 (m, 6H), 1.7 (m, 6H), 2.9 (q, J=7 Hz, 2H), 4.6 and 4.7 (s, 2H), 12.1 (bs, 1H); MS (EI): M+ 252.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:32]1([NH:42]N)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:33]4[C:32](=[C:41]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]5=[CH:35][CH:34]=4)[NH:42][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 530.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C.C1COCC1>[OH:3][CH:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1cnc(NC(=O)C(C)(C)C)cn1
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
To a solution of N-(5-acetylpyrazin-2-yl)-2,2-dimethylpropanamide (500 mg) in ethanol (10 mL) and THF (10 mL) was added sodium borohydride (86 mg) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture was added 1 M hydrochloric acid under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to obtain N-[5-(1-hydroxyethyl)pyrazin-2-yl]-2,2-dimethylpropanamide (525 mg) as a brown solid.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[O:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH2:7]1.C1COCC1.CC(C)([O-])C.[K+]>CCOC(C)=O.O.C(O)(C)(C)C>[N+:1]([CH:4]([CH3:5])[CH:12]([CH:9]1[CH2:10][CH2:11][O:6][CH2:7][CH2:8]1)[OH:13])([O-:3])=[O:2]
Reactant: O=CC1CCOCC1
Reactant: CC[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C(O)C1CCOCC1)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
In a 100 mL round-bottomed flask, nitroethane (1.42 ml, 26.3 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (1.0 g, 8.76 mmol) were combined with THF (5 ml) and tert-butanol to give a colorless solution. Potassium tert-butoxide (197 mg, 1.75 mmol,) was added at room temperature. After 30 min at room temperature, the reaction mixture was diluted with EtOAc and water. The organic phase was separated, dried, and evaporated to provide 1.3 g (79%) of crude 2-nitro-1-(tetrahydro-pyran-4-yl)-propan-1-ol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 4.74 (quin, J=6.61 Hz, 1H), 4.61 (qd, J=6.80, 3.02 Hz, 1H), 3.91-4.10 (m, 7H), 3.60 (t, J=5.48 Hz, 1H), 3.28-3.54 (m, 3H), 2.20-2.28 (m, 3H), 1.89-2.00 (m, 4H), 1.11-1.74 (m, 16H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8](Cl)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].C([O-])(=O)C.[K+].CCCCCC.C(OCC)(=O)C>CO.[Pd].[C]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
A solution of 1.00 g (0.003 mole) of 2-butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-formylimidazole in 75 mL of methanol is reduced at low pressure with hydrogen and 0.30 g of 5% Pd/carbon in the presence of 0.30 g of potassium acetate to give product; mp 62°-64° C.; tlc (1:1 hexane-ethyl acetate) 1 spot, Rf 0.2; MS (CI) 301 (M+ +1).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[Br:12][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)[nH]n1
Solvent: CC#N
Product: CCOC(=O)c1n[nH]c(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5-methyl-1H-pyrazole-3-carboxylate (3.24 g) in CH3CN (25 mL) was treated with N-bromosuccinimide (3.92 g) at 0° C. The solution was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by flash chromatography on silica gel (ethyl acetate in hexanes) to give the title compound. 1H NMR (500 MHz, DMSO-d6): 13.61 (s, 1H), 4.27 (q, J=6.75 Hz, 2H), 2.21 (s, 3H), 1.28 (t, J=7.06 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:56][CH2:57][CH2:58][N:59]1[CH2:63][CH2:62][CH:61]([NH:64][C:65](=[O:67])[CH3:66])[CH2:60]1>CN(C=O)C>[C:65]([NH:64][CH:61]1[CH2:62][CH2:63][N:59]([CH2:58][CH2:57][NH:56][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:60]1)(=[O:67])[CH3:66]
Reactant: CC(=O)NC1CCN(CCN)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(CCNC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)C1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (252 mg, 0.5 mmol) in DMF (10 mL) was added HOBt (101 mg, 1.5 eq.), EDAC.HCl (144 mg, 1.5 eq.) and TEA (152 mg, 3 eq.). After stirring at rf for 30 mins, to the mixture was added N-[1-(2-amino-ethyl)-pyrrolidin-3-yl]-acetamide (128 mg, 1.5 eq.). After stirring at 30° C. for 72 hours, the reaction was concentrated and the residue was purified on a silica gel column to give 213 mg (65%) of the titled compound as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.[C:17](O)([C:19]([F:22])([F:21])[F:20])=[O:18]>C(N(CC)CC)C>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:17](=[O:18])[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Solvent: CCN(CC)CC
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)C(F)(F)F
Yield: 20 %

Procedure:
To a solution of 10-methoxyharmalan (40 mg) in triethylamine (1 ml) is added TFA (2.2 eq). After reaction for 15 min. at 0° C., the mixture is hydrolysed and extracted with CH2Cl2. The crude product is then chromatographed on a preparative plate (eluent: CH2Cl2). 1-Methylene-2-trifluoroacetyl-6-methoxy-1,2,3,4-tetra-hydro-β-carboline is recovered (yield: 20%).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: NC1CCC1
Solvent: CCO
Product: OCC1CC(n2c(NC3CCC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (7 mL) and cyclobutylamine (0.41 mL, 4.8 mmol) was added. The solution was refluxed under nitrogen for 18 hours. Volatiles were evaporated and the residue stirred in methanol half-saturated with ammonia at 0° C. (20 mL) for 18 hours. Volatiles were removed in vacuo and the residue crystallized from ethanol-water to give title compound as white solid, m.p. 250° C. dec.; 1H-NMR(DMSO-d6)δ: 7.61 and 7.38 (both s, 1 each, aromatic CH), 7.07 (d, J=7.4 Hz, 1, NH), 5.15 (t, J=3.9 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.71-4.45 (m overlapping d at 4.71, J=3.5 Hz, total 2, OH and NCH), 4.40-4.30 (m, 2. OCH and NCH), 3.82-3.80 (m, 1, OCH), 3.72-3.42 (both m, 1 each, OCH2), 2.32-1.67 (three m, 9, 4CH2 and CH); mass spectrum (CI): 386(M +1).
Reaction SMILES: B(O)(O)O.O.[B:6]([O:9][B:10]([OH:12])[OH:11])([OH:8])[O-:7].[NH4+:13].Br([O-])(=O)=O.Br([O-])(=O)=O.[NH4+].[NH4+]>>[B:6]([O:9][B:10]([OH:12])[OH:11])([O-:8])[O-:7].[NH4+:13].[NH4+:13]
Reactant: [O-]B(O)OB(O)O
Agent: OB(O)O
Agent: [NH4+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Product: [O-]B([O-])OB(O)O

Procedure:
100 gms of boric acid are heated to 160° C. to 200° C. until three mols of water is removed per molecule thereby producing boron oxide (B2O3). The powdered boric oxide is slowly added to 100 gms of aqueous ammonia containing 25 % ammonia while agitating and keeping the temperature below the temperature wherein the ammonia evaporates from the water. Increase pressure may also be used to prevent the loss of ammonia from the water and the ammonia may be added to the water in a gaseous form. The mixture is allowed to react for 1-4 hours thereby producing a mixture of monoammonium diborate, diammonium dibromate, polyammonium dibromate and ammonium salt of boric acid. The mixture is dried and the ammonium salt of boric acid condensates to form diammonium diborate. The mixture is pulverized into a fine powder.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([N+:25]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1.[H][H]>CN(C)C=O.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([NH2:25])[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1
Reactant: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2N)cc1

Procedure:
203 gm of 5-methyl-6-[3-nitro-4-(4-methoxy-benzoylamino)-phenyl]-4,5-dihydro-2H-pyridazine-3-one were dissolved in 1.7 liters of dimethylformamide, and the solution was treated with hydrogen in the presence of 20 gm of 10% palladium charcoal for 2 hours at a pressure of 5 bar. After filtering off the catalyst, the filtrate was poured into 7.5 liters of ice water. The precipitated product was dried at 120° C.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][C@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]1[OH:20])#[N:2].[CH3:23][NH:24][CH3:25]>>[C:1]([N:3]=[C:4]([N:24]([CH3:25])[CH3:23])[NH:5][C@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]1[OH:20])#[N:2]
Reactant: CSC(=NC#N)N[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Reactant: CNC
Product: CN(C)C(=NC#N)N[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O

Procedure:
A mixture of (3R,4S)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.12 g) and 50% aqueous dimethylamine solution (10.6 ml) was stirred under reflux for 1.5 hours to form white precipitates. These precipitates were collected by filtration, washed with water, and recrystallized from ethanol to give (3R, 4S)-4 -(2-cyano-3,3-dimethylguanidino)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.03 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH3:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.[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>[CH3:12][O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: C#C[Si](C)(C)C
Reactant: COC1(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) and anhydrous tetrahydrofuiran (4 mL) was treated with copper(I)iodide (93.0 mg, 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.39 g, 14.2 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). The resulting reaction mixture was heated to 70° C. for 60 h. The title compound (286.0 mg, 90%) was isolated by chromatography (0-3% EtOAc-hexanes).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[CH3:29]C(C)([O-])C.[K+].CI>CS(C)=O>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:29])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: COc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 36)(72 mg, 0.181 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (20 mg, 0.178 mmol). The reaction mixture was stirred for 5 min before adding methyl iodide (0.011 ml, 0.181 mmol, Aldrich). The reaction was stirred at ambient temperature, overnight and under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a white solid (20.3 mg);
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH:6]([C:8]([CH2:10][CH3:11])=[O:9])=[CH2:7].C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1.[CH2:32]([O:39][C:40](=[O:46])[NH:41][CH:42]=[CH:43][CH:44]=[CH2:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C.CCOCC>[C:8]([C@H:10]1[C@@H:42]([NH:41][C:40](=[O:46])[O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:43]=[CH:44][CH2:45][CH2:11]1)(=[O:9])[CH2:6][CH3:7]
Reactant: C=CC=CNC(=O)OCc1ccccc1
Reactant: C=CC(=O)CC
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Solvent: CCOCC
Product: CCC(=O)[C@@H]1CCC=C[C@@H]1NC(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 84 h
Yield: 91 %

Procedure:
Concentrated (70% aqueous) perchloric acid (431 μL, 5.0 mmol) was added slowly to a stirring solution of ethyl vinyl ketone (2.49 mL, 25.0 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (1.35 g, 5.0 mmol) pre-chilled to −30° C. Then, buta-1,3-dienyl-carbamic acid benzyl ester (4.47g, 31.3 mmol) was added dropwise over 15 minutes as a solution in 12.5 mL of absolute ethanol. After stirring for 3.5 days, the reaction was diluted with ether (150 mL), washed successively with 1N HCl (50 mL), water (50 mL) and brine (25 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a pale brown oil. Purification by silica gel (8:1 hexanes:ethyl acetate) afforded the title compound as a single diastereomer (as judged by HPLC analysis) in 91% yield (5.17g, 22.7 mmol) and 98% ee. The combined aqueous extracts were treated with solid K2CO3, extracted with 3×50 mL portions of CHCl3, dried over anhydrous Na2SO4 and concentrated in vacuo to afford a 91% recovery of (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (1.23 g, 4.55 mmol) after silica gel chromatography. IR (film) 3411, 3329, 3064, 3031, 2974, 2938, 2879, 2836, 1956, 1872, 1711, 1523, 1455, 1409, 1376, 1331, 1278, 1236, 1164, 1120, 1060, 1028, 988.9, 973.1, 775.6, 736.0, 697.9 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.33 (m, 5H, ArH), 5.82 (m, 1H, CH═CH), 5.70 (m, 1H, CH═CH), 5.04 (m, 3H, CH2Ph and NH), 4.63 (m, 1H, CHNH), 2.86 (ddd, J=10.2, 3.9, 3.9 Hz, 1H, CHCO), 2.70 (dq, J=18.0, 7.2 Hz, 1H, one of CH2CO), 2.43 (dq, J=17.7, 7.2 Hz, 1H, one of CH2CO), 2.10-1.65 (m, 4H, CH2CH2), 1.00 (dd, J=6.9, 6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 212.0, 155.9, 136.6, 130.1, 128.7, 128.2, 128.1, 126.9, 67.0, 50.4, 46.9, 34.8, 24.2, 20.7, 8.0; HRMS (CI) exact mass calc'd for (C17H21NO3) requires m/z 287.1521, found m/z 287.1519. [α]D=+122.0 (c=1.0, CHCl3). Product ratios were determined by HPLC analysis (OD-H column, 3% ethanol in hexanes, 1 mL/min, 254 nm); (1S, 6R) endo isomer tr=12.5 min, and (1R, 6S) endo isomer tr=11.3 min, exo isomers tr=8.6, 9.2 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1.C(N(CC)CC)C.O>C1COCC1>[CH3:1][S:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1)(=[O:4])=[O:3]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)n1nc(C(=O)O)c2ccccc21
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (48.1 μl, 0.617 mmol) was added to a solution of 1H-indazole-3-carboxylic acid (100 mg, 0.617 mmol) and triethylamine (86 μl, 0.617 mmol) in THF (1542 μl) and the mixture was stirred for 1 h. The reaction was then poured into water and extracted twice with EtOAc. The combined organic layers were filtered through MgSO4 and concentrated to give the title compound as a white solid, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:8][CH:9]([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(OCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
Diethyl benzyloxymalonate (6.0 g., 22.6 mmoles) was added to an ice cold solution of potassium hydroxide (2.66 g., 47.5 mmoles) in absolute ethanol. The mixture was stirred until a homogenous mixture was obtained and stirring continued for an additional 30 minutes in a cold environment. Stirring was thereafter conducted under an atmosphere of argon at room temperature for about 16 hours. The product was filtered, washed with ethanol, and diethyl ether and then dried under vacuum to yield the dipotassium salt of benzyloxymalonic acid (4.4 g., 15.4 mmoles, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([NH:19][CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(O)(=O)C.ClCCCl.C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([N:19]([CH2:32][CH:29]2[CH2:31][CH2:30]2)[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: O=CC1CC1
Reactant: CNC1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(CC1CC1)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (±)-2-chloro-N-[[1-(methylamino)cyclopentyl](phenyl)methyl]-3-(trifluoromethyl)benzamide E22 (143 g; 0.35 mmol), cyclopropanecarboxaldehyde (0.026 ml; 0.035 mmol) and acetic acid (3 drops) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (303 mg; 1.4 mmol). The resulting mixture was allowed to stir at room temperature under argon overnight. Then the reaction mixture was diluted with DCM (20 ml), washed with saturated potassium carbonate solution and brine, dried (Na2SO4) and evaporated in vacuo. The mixture was separated by column chromatography on silica gel using 20% ether in n-pentane to 2% methanol in ether. The oil obtained was treated with 1M HCl in ether to give the title product as an off white hydrochloride salt (0.054 g; 33%). Mass Spectrum (Electrospray LC/MS). Found 465 (MH+). C25H2835ClF3N2O requires 464. Ret. time: 2.30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.BrBr.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][S:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)C1=NN(c3ccc(Cl)cc3)C(=O)CC1CS2
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(c1)-c1nn(-c3ccc(Cl)cc3)c(=O)cc1CS2
Yield: 29.6 %

Procedure:
To a mixture of 1.7 g of 2-(4-chlorophenyl)-9-methyl-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one in 30 ml of acetic acid is added 1.2 g of bromine dropwise with stirring at 40°-50° C. on a water bath. After the completion of addition, the mixture is stirred at 50° C. for 3 hours and poured into an excess amount of water. The precipitated crystals are collected by filtration and recrystallized from acetic acid to give 0.5 g of 2-(4-chlorophenyl)-9-methyl-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one, melting at 200°-206° C., as a yellow powder.