Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)C(=O)OC(C)(C)C)[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[C:15]([NH:17][CH:25]2[CH2:26][CH2:27]2)[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1)[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N(c1cc(Nc2ccc(C#N)cc2Br)nc2c(C=O)cnn12)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)c(Br)c1
Reaction time: 1 h
Yield: 67 %

Procedure:
Tert-butyl 5-(2-bromo-4-cyanophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (105 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. After 1 h, the reaction was concentrated to dryness and the residue was triturated with Et2O. The yellow solid was collected and dried to give 3-bromo-4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile 2,2,2-trifluoroacetate (72 mg, 67%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[S:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: COc1cc(C)c(C)cc1NC(=S)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 85 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][N:15]([CH3:21])[C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(OCC)(=O)C>C1COCC1>[CH3:14][N:15]([CH3:21])[CH:16]1[CH2:20][CH2:19][N:18]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Yield: 47.5 %

Procedure:
Suspend 2-chloro-6-nitrobenzthiazole (8.49 g, 39.6 mmol) in THF (100 mL). Slowly add (3R)-(+)-3-(dimethylamino)pyrrolidine (5.24 g, 45.9 mmol). Stir the reaction overnight at room temperature. Dilute the reaction with ethyl acetate and then wash with water and brine. Concentrate the organic portion in vacuo, and triturate the resulting residue with MeOH to afford the title compound (4.94 g, 43%). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, 1H, J=2.2 Hz), 8.14 (dd, 1H, J=9.0, 2.4 Hz), 7.52 (d, 1H, J=8.8 Hz), 4.00-3.43 (m, 3H), 3.30 (m, 1H), 2.91 (m, 1H), 2.20-2.15 (m, 7H), 1.93 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][CH:9]1[N:17](CC2C=CC(C(O)(C)C)=CC=2)[CH:16]=[CH:15][CH:14]=[C:10]1[C:11]([OH:13])=O)=[O:4].[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([OH:44])([CH3:42])[CH3:43])=[CH:37][CH:36]=1)=[O:13])=[O:4]
Reactant: CN(C)C(=O)c1cccc(OC2C(C(=O)O)=CC=CN2Cc2ccc(C(C)(C)O)cc2)c1
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)c1

Procedure:
To a stirred solution of 2-(3-Dimethylcarbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinic acid (0.300 grams, 1.05 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.190 grams, 1.15 mmole), and 1-hydroxybenzotriazole hydrate (0.155 grams, 1.15 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.242 grams, 1.26 mmole) and stirred over night. The mixture poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanollmethylene chloride (0.360 g). 1H NMR (CDCl3) d 1.54 (6H, s), 3.00 (3H, s), 3.08 (3H, s), 4.66 (2H, d), 7.20 (3H, m), 7.29 (4H, m), 7.43 (2H, m) 8.08 (1H, m), 8.18 (1H, dd), 8.63 (1H, dd); MS: m/e 433 (M+).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.Br[CH2:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH:1]1([C:7]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[CH3:25])=[CH:15][N:9]3[C:8]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CC(Cc2ccccn2)CCC1
Reactant: Cc1c(F)cccc1CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1c(F)cccc1Cc1cn2ccccc2c1C1CCCCC1
Yield: 64.2 %

Procedure:
The compound of step 1 (0.415 g, 2.37 mmol) and the compound of step 2 of example 1 (0.58 g, 2.37 mmol) were dissolved in 15 ml of acetone and the solution was stirred under reflux for 36 h. The solution was evaporated to dryness and the solid (0.92 g) dissolved in 10 ml of isopropanol. Sodium carbonate (0.70 g, 6.57 mmol) was added, the mixture was stirred under reflux for 2 h and then evaporated to dryness under reduced pressure. The residue was taken up in DCM and water, and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (HEP/EA, 100:0, then 70:30) to give 0.489 g of the title compound as a thick yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:7]=[CH:6][NH:5][N:4]=1)#[N:2].C(O[C@@H:12]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]1[O:14][C:15](=[O:17])[CH3:16])(=O)C.P([O-])(OC1C=CC([N+]([O-])=O)=CC=1)(OC1C=CC([N+]([O-])=O)=CC=1)=O>C(Cl)(Cl)Cl>[C:1]([C:3]1[N:7]=[CH:6][N:5]([C@@H:12]2[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]2[O:14][C:15](=[O:17])[CH3:16])[N:4]=1)#[N:2]
Reactant: N#Cc1nc[nH]n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.25 h

Procedure:
A mixture of 3-cyano-1,2,4-triazole (9.41 g., 0.10 mol) and 1,2,3,5-tetra-O-acetyl-β -D-ribofuranose (31.8 g., 0.10 mol) was heated in an oil bath maintained at 150°. Bis(p-nitrophenyl) phosphate (100 mg.) was added with stirring and heating at 150° under diminished pressure was continued for 15 min. The residue was dissolved in chloroform, the solution was filtered and the solvent was removed. Crystallization of the residue from ether provided 28.2 g. (80%) of product with M.P. 96-97°.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:25])([F:24])[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=1)=[O:9]>C(Cl)Cl>[Cl:1][S:2]([C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]([F:25])([F:24])[F:6])=[CH:12][C:13]=1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:5])=[O:3]
Reactant: CCOC(=O)CCc1cccc(NC(=O)C(F)(F)F)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Yield: 30.6 %

Procedure:
ClSO3H (2 g, 17.3 mmol) was cooled to 0° C. and ethyl 3-(3-(2,2,2-trifluoroacetamido) phenyl)propanoate (1 g, 3.46 mmol) was added portionwise with vigorous stirring keeping the temperature below 5° C. The reaction mixture was stirred at room temperature overnight, and cautious poured onto ice. The solid produced was dissolved in CH2Cl2. The combined organic phase was washed with saturated NaHCO3 and saturated brine, dried over MgSO4 to give the product ethyl 3-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)phenyl)propanoate (0.41 g, yield 31%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][C:17]([Cl:23])=[O:19])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1c(Cl)cccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCc1c(Cl)cccc1-c1ccccc1
Reaction time: 18 h

Procedure:
Under a dry argon atmosphere a stirred solution of 4-(3-chloro[1,1'-biphenyl]-2-yl)butanoic acid (22.8 g, 0.083 mole) in toluene (500 ml) was heated at 65°. Oxalyl chloride (21 g, 0.166 mole) was added slowly to the reaction mixture. After complete addition the mixture was allowed to stir at 40° for approximately 18 hours. The solvent and excess oxalyl chloride were removed by distillation under reduced pressure. Further distillation under reduced pressure gave 4-(3-chloro[1,1'-biphenyl]-2-yl)butanoic acid chloride (b.p. 150°/0.04 mm) as a clear oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Reactant: CC(C)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(-c3nnnn3CC(C)C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.150 g, 0.428 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.019 g, 0.479 mmol, 60% in mineral oil). Let stir for 1 h, then add 1-bromo-2-methylpropane (0.052 mL, 0.479 mmol) and let stir overnight. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×15 mL). Combine the organic layers and wash with brine (2×20 mL), aqueous NH4Cl (1×20 mL), aqueous NaHCO3 (1×20 mL) and water (1×20 mL). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the residue via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes). Concentrate under reduced pressure the purified fractions and azeotroped with methylene chloride/hexanes. Place the residue under vacuum to provide the title compound as a colorless tar (0.011 g); mass spectrum (m/e): 407.3 (M+H)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)[nH]c1N
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere, 1.65 g (1 0 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride (for preparation see: Liebigs Ann. Chem., 1895 (1977)) are introduced into 10 ml of ethanol and, at 0-5° C., 0.73 g (10 mmol) of sodium ethanolate is added thereto. The bright yellow suspension is stirred for 20 min and then 1.4 g (5 mmol) of 2-bromo-1-(biphen-4-yl)-ethan-1-one (2-bromo-4'-phenyl-acetophenone; Aldrich; Milwaukee/USA) are added thereto. After 48 hours' stirring at RT, the reaction mixture is concentrated by evaporation and the residue is taken up in ethyl acetate and washed with 3 portions of water and brine. The aqueous phases are extracted twice with ethyl acetate and the organic phases are dried over MgSO4 and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diisopropyl ether/hexane yield the title compound; m.p. 186-188° C.; TLC-Rf =0.17 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =306.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:12]=[CH:11][C:9]([NH2:10])=[N:8][C:6]2=[O:7])[CH2:3][CH2:2]1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21](Cl)(=[O:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(#N)C>C(N(CC)CC)C>[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21]([NH:10][C:9]2[CH:11]=[CH:12][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:7])[N:8]=2)(=[O:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccn(CC2CC2)c(=O)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccn(CC3CC3)c(=O)n2)cc1

Procedure:
A mixture of 495 mg. of 1-cyclopropylmethylcytosine, 702 mg. of N-acetylsulfanilyl chloride, 10 ml. of acetonitrile and 322 mg. of triethylamine was stirred and refluxed for 18 hours. The solvent was evaporated under reduced pressure, and the residue triturated with 10 ml. of water and 3 ml. of 10% aqueous sodium hydroxide. The alkaline solution was decanted from the dark insoluble portion and cleared by filtration. Addition of acetic acid to about pH 5 gave a gummy precipitate which solidified only very slowly. The aqueous solution was decanted and the gum triturated with 2 ml. of hot ethanol, and allowed to settle in an ice bath to obtain after filtration 280 mg. of product, melting at 222°-224°. A sample for analysis was recrystallized from aqueous ethanol; m.p. 225°-226°.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][C:19]1[O:23][C:22]([CH:24]([C:26]2([CH3:30])[CH2:29][O:28][CH2:27]2)O)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:15]([CH:24]([C:26]1([CH3:30])[CH2:29][O:28][CH2:27]1)[C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)=[N+:16]=[N-:17]
Reactant: Cc1ccc(C(O)C2(C)COC2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C(N=[N+]=[N-])C2(C)COC2)o1
Temperature: 0 °C
Reaction time: 23 h
Yield: 47.7 %

Procedure:
5.30 g (19 mmol, 1.1 eq) of diphenylphosphoryl azide were added dropwise to a solution of 3.02 g (17 mmol, 1 eq) of (5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methanol in 50 ml of toluene. The reaction medium was cooled to 0° C. and then 2.9 ml (19 mmol, 1.1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise. The reaction medium was stirred at ambient temperature for 23 hours. The reaction medium was separated by settling out and the organic phase was washed with water and then with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column Analogix SF40-150 g, Spot II) eluted with heptane/ethyl acetate (95/5). 1.68 g of 2-[azido-(3-methyloxetan-3-yl)methyl]-5-methylfuran were obtained in the form of an orange oil. Yield=48%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH:11]=O)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C
Reaction time: 4 h

Procedure:
A solution of (3S*,4S*)-4-formyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.87 g, 10.56 mmol) and isopropylamine (2.72 mL, 31.68 mmol) in 1,2-dichloroethane (150 mL) is stirred 25 min, before addition of NaBH(OAc)3 (3.12 g, 14.78 mmol) follows. The solution is stirred for 4 h, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The combined organic extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 80:20) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.1.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[CH:24]1[C:37]2[C:36]3([CH2:39][N:40]4[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]4)[CH2:38][CH:29]([C:30]4[C:35]3=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:28]=2[CH:27]=[CH:26][CH:25]=1>O1CCCC1.N1C=CC=CC=1>[CH:34]1[C:35]2[C:36]3([CH2:39][N:40]4[CH2:45][CH2:44][C:43]([C:23]5[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=5)([OH:46])[CH2:42][CH2:41]4)[CH2:38][CH:29]([C:28]4[C:37]3=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccccn1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a cooled solution (-72° C.) of t-butyllithium (1.7M in pentane, 5.38 mL, 9.15 mmol, 2.8 eq) in tetrahydrofuran (24 mL) under nitrogen was added dropwise bromomesitylene (0.64 mL, 4.18 mmol, 1.3 eq). The metal-halogen exchange reaction was stirred for an additional hour during which time a white precipitate forms. 2-Methoxypyridine (0.50 g, 4.38 mmol, 1.4 eq) was added to this suspension and the resulting reaction was warmed to room temperature and stirred at that temperature for 4 h. The metallated pyridine solution was recooled to -72° C. and a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (1.00 g, 3.3 mmol) in tetrahydrofuran (3 mL) was added. The reaction was warmed to room temperature over 1.5 h. After stirring for 18 h, the reaction was quenched with the addition of water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried with anhydrous sodium sulfate, filtered, and reduced to an oil. The product was purified by flash chromatography over silica gel (100 mL, eluent: 30% ethyl acetate in hexane) to yield 0.99 g (73%) of the title compound as a white solid. TLC analysis (Rf 0.23, 30% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 8.05 (dd, J=4.9, 1.7 Hz, 1H), 7.49 (dd, J=7.5, 5.7 Hz, 1H), 7.22 (m, 4H), 6.92 (m, 5H), 4.27 (s, 1H), 4.02 (s, 3H), 3.78 (s, 1H), 3.48 (s, 2H), 2.83 (m, 4H), 2.61 (d, J=1.4 Hz, 2H), 2.00 (m, 4H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,13), 395 (24). The free base was dissolved in methylene chloride, diluted with ether and acidified with ethereal HCl. The resulting hydrochloride salt was filtered, rinsed with fresh ether, and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 225°-228° C. (dec).
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]1[CH:12]2[CH:13]3C=CC([CH:11]2C=[CH:9]1)C3>>[CH2:5]([C:2]1([CH:3]=[O:4])[CH2:11][CH:12]2[CH2:13][CH:1]1[CH:9]=[CH:8]2)[CH2:6][CH3:7]
Reactant: C=C(C=O)CCC
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: CCCC1(C=O)CC2C=CC1C2
Temperature: 170 °C
Yield: 44.9 %

Procedure:
2-Methylene pentanal (302 g) and dicyclopentadiene (244 g) were loaded into a 2-L autoclave. The autoclave was sealed and heated to 170° C. The reaction was monitored by Gas Chromatography (“GC”) analysis, which showed the completion after 3 hours. The reaction was cooled to room temperature. The crude product was purified by distillation to yield 2-propylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde (136 g).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]([CH3:21])/[CH:8]=[CH:9]/[C:10]([C:12]1[CH:13]=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12)=O.[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[Na+]>C(Cl)Cl.CO>[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[Cl:3]/[C:10](/[C:12]1[CH:13]=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12)=[CH:9]\[CH:8]=[N+:7]([CH3:21])[CH3:6]
Reactant: CN(C)/C=C/C(=O)c1cnn2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[N+](C)=C/C=C(\Cl)c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
POCl3 (0.951 mL, 10.20 mmol) was added to a solution of (E)-3-(dimethylamino)-1-(pyrazolo[1,5-a]pyridin-3-yl)prop-2-en-1-one (2.153 g, 10 mmol) in CH2Cl2 (15 mL) at 20° C. (using ice/water cooling) over a period of 3 minutes under N2. The resulting solution was stirred at r.t. for 0.5 h and was then concentrated in vacuo. The residue was dissolved into a minimum amount of CH3OH (100 mL). This solution was added over a period of 2 minutes to a solution of sodium hexafluorophosphate(V) (3.36 g, 20.00 mmol) in CH3OH (40 mL). After 5 minutes the precipitate was collected by filtration, washed well with CH3OH cooled to −50° C. and dried by suction under a stream of N2 to give the title compound (3.40 g, 90%) as a yellow powder, which was used without further purification; 1H NMR: 3.63 (6H, d), 7.36 (2H, m), 7.71-7.90 (1H, m), 8.45 (1H, d), 8.81 (1H, d), 9.05 (2H, d); m/z: ES+ M+ 234.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[CH:7]=1)(=O)C.[CH3:18][S:19]([O-:21])=[O:20].[Na+]>CC(C)=O.O>[CH3:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([CH2:5][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:7]1
Reactant: CS(=O)[O-]
Reactant: CC(=O)OCc1cn(C)c2ccccc2c1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21

Procedure:
To a solution of 3-acetoxymethyl-1-methyl-4-quinolone (0.8 g.) in acetone (15 ml.) was added a solution of sodium methanesulphinate (0.53 g.) in water (10 ml.). The mixture was boiled under reflux for 24 hours. Further sodium methanesulphinate (0.14 g.) was added and the mixture was boiled under reflux for 4 hours. Acetone was evaporated from the mixture, causing the separation of a white solid which was recrystallised from industrial methylated spirit to give 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 195°-197°.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(O[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:22]([N:16]1[CH2:17][CH:6]2[CH:7]([C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4][C:5]2=[O:8])[CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(=O)C2CN(Cc3ccccc3)CC21
Reaction time: 3 h

Procedure:
To a solution of 5 g of 4,4-dimethylcyclohex-2-enone and 12.4 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 100 cm3 of dichloromethane are added, at a temperature of 10° C., 5 drops of trifluoroacetic acid. The reaction mixture is stirred at this temperature for 3 hours, then potassium carbonate is added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 5.2 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 100 cm3 fractions. Fractions 39 to 63 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.64 g of (3aRS,7aRS)-2-benzyl-7,7-dimethyl-4-perhydroisoindolone are obtained in the form of a yellow oil.