Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>>[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[NH:7][C:20](=[O:21])[C:19]1[C:18]([F:17])=[CH:26][CH:25]=[CH:24][C:23]=1[F:27])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1c(F)cccc1F

Procedure:
L-Tyrosine ethyl ester hydrochloride (10.0 g) was acylated with 2,6-difluorobenzoyl chloride in a similar manner as described in Example 1-(5) to give N-(2,6-difluorobenzoyl)-L-tyrosine ethyl ester (13.2 g). mp. 149-150° C.; IR (Nujol) 3424, 3277, 1721, 1660, 1624 cm−1; MS (APCI) m/z 350 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C=O.[C:24]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH3:24])[CH2:20][CH3:21]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
309 mg (1.07 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) was added dropwise in a 100 ml recovery flask, and dissolved in 9.2 ml of anhydrous methanol. 0.134 ml of a formaldehyde aqueous solution (35%) was then added to the solution. 201.7 mg of sodium cyanoborohydride was then added to the mixture. After the addition of acetic acid to adjust the mixture to pH 5.0, the mixture was stirred at room temperature for 24 hours. 1 mol/l sodium hydroxide aqueous solution was then added to the mixture, followed by extraction with chloroform. The extract was dried over magnesium sulfate and concentrated, thereby obtaining 296.2 mg of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b) was obtained as a colorless oily substance (yield: 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([N:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)CC(=O)NC(=O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=O)N(Cc2ccccc2)C(=O)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 4,4-dimethylpiperidine-2,6-dione (2.0 g, 14.2 mmol) in acetone (50 mL) was added K2CO3 (3.92 g, 28.3 mmol) followed by (bromomethyl)benzene (1.85 mL, 15.6 mmol). The reaction mixture was heated at 50° C. for 4 h then cooled to room temperature and stirred overnight. The thick white precipitate present was removed via filtration, rinsing with acetone. The filtrate was concentrated and purified by SiO2 chromatography (10% to 50% EtOAc/hexanes) to afford 3.0 g (92%) of 1-benzyl-4,4-dimethylpiperidine-2,6-dione as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[CH:8]12[NH:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][O:10][CH2:9]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:7][C:5]1[N:6]=[C:2]([N:15]2[CH:8]3[CH2:14][CH2:13][CH:12]2[CH2:11][O:10][CH2:9]3)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: C1CC2COCC1N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1csc(N2C3CCC2COC3)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
To a stirred solution of 2,4-dibromothiazole (0.585 g, 2.41 mmol) in DMF (10 ml) were added 3-oxa-8-azabicyclo[3.2.1]octane (prepared according to the procedure given in WO 2010/120854, 0.3 g, 2.65 mmol) and DIPEA (0.47 gm, 0.63 ml, 3.62 mmol) under a stream of nitrogen. The reaction mixture was then stirred at 80° C. for 18 hrs and the progress of reaction was monitored by TLC. The reaction mixture was cooled to room temperature; quenched with cold water (20 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with water (2×10 ml), dried over sodium sulphate and concentrated to give crude compound; which was purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.31 g, 46.7%). MS: m/z 276 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([CH3:14])[C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:20](Cl)Cl>>[C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([C:9]([O:11][CH3:20])=[O:10])=[C:12]([CH3:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: Cc1cc(C(C)(C)C)cc(C)c1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(C)cc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To 50 g (0.26 moles) of 4-t-butyl-2,6-dimethylbenzoic acid in 250 ml methylene chloride was added 25 ml (0.34 mole) of thionyl chloride at 25° C. After stirring overnight at 25° C. the solvent and remaining thionyl chloride were evaporated in vacuo. The resulting white solid was dissolved in 50 ml tetrahydrofuran and added dropwise to 250 ml of methanol containing 2 ml of pyridine. After heating the reaction mixture to reflux for 30 minutes the solvents were evaporated in vacuo and the residue was dissolved in 200 ml ethyl acetate and 100 ml of water was added. The organic phase was separated and washed with 100 ml saturated aqueous sodium bicarbonate, 50 ml water and 25 ml brine; then dried over anhydrous magnesium sulfate and evaporated to an oil. The oil was distilled in vacuo at 104°-8° C. at 1.2 mm of mercury to obtain 43 g (81% yield) of the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:12])[CH2:10][CH3:11])[C:3]([O:5]CC)=O.[Cl-].C[C:15](=[NH2+:17])C.N>>[OH:1][C:2]1[C:3](=[O:5])[NH:17][CH2:15][C:8]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CC(C)=[NH2+]
Agent: N
Agent: [Cl-]
Product: CCC(=O)C1=C(O)C(=O)NC1

Procedure:
Reaction of ethyl 2,4-dioxohexanoate with dimethylmethylene ammonium chloride and ammonia, analogous to the procedure in Preparation 8, gave the title compound as an amorphous solid. 1H nmr (250 MHz, DMSO-d6) δ0.99 (t, J=7.3 Hz, 3H), 2.75 (q, J=7.3 Hz, 2H), 3.81 (s, 2H), 8.84 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][C:15]([C:22]([F:25])([F:24])[F:23])([C:19](F)=[O:20])[C:16](F)=[O:17]>C(COC)OC>[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][C:15]1([C:22]([F:23])([F:24])[F:25])[C:16](=[O:17])[NH:4][C:2](=[O:3])[NH:1][C:19]1=[O:20]
Reactant: NC(N)=O
Reactant: CC(C)=CCC(C(=O)F)(C(=O)F)C(F)(F)F
Solvent: COCCOC
Solvent: c1ccncc1
Product: CC(C)=CCC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 0.96 g (0.016 mol) of urea, 2.45 g (0.031 mol) of pyridine and 20 ml of glyme was stirred at 25°C while 3.8 g (0.0155 mol) of (3-methyl-2-butenyl)trifluoromethylmalonyl fluoride in 10 ml of glyme was added rapidly. The mixture was stirred overnight, heated for 10 minutes at 70°C, and evaporated to a viscous residue. Trituration of the residue with 20 ml of water gave 2.7 g (66%) of 5-(3-methyl-2-butenyl)-5-trifluoromethylbarbituric acid, mp 150°-153°C. A sample for analysis was recrystallized from water, mp 154°-155°C; ir (KBr): 3.04 and 3.18 (NH), 3.32, 3.39 and 3.44 (CH), 5.63 and 5.81 (C=O), and 8-8.5 μ (CF). Raman ir spectrum showed C=C at 5.95 μ; nmr ((CD3)2CO): 1H at ca. 9.0 (very broad (partly exchanged into acetone-d6), 2, NH), 5.03 (triplet, JHH = 7.7 Hz, 1, =CH), 3.07 (doublet, JHH = 7.7 Hz, 2, =CCH2), 1.69 and 1.67 ppm (singlets, 6, =CCH3); 19F at -69.0 ppm (singlet, CF3).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.46 g, 6.42 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.257 g, 6.42 mmol) dissolved in water (2 mL) was added over 5 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.4 mL, 6.53 mmol) was added over 1 min and stirring continued at −40° C. for 1 h 15 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 35 min. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-60% Acetonitrile in H2O/MeCN/Acetic Acid 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.62 g, 72%) was isolated as a colorless foam. 1H NMR (400 MHz, cd3od) δ 1.90-2.10 (m, 4H), 2.65-2.80 (m, 2H), 3.04 (p, 1H), 3.19-3.34 (m, 1H), 3.44 (s, 3H), 3.94 (ddd, 1H), 4.32-4.44 (m, 1H), 5.85 (s, 1H), 6.78-6.90 (m, 2H), 7.09-7.20 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[O:17]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCc1ccc(Oc2ccccc2)cc1
Product: O=c1c(NCc2ccc(Oc3ccccc3)cc2)c(Nc2ccncc2)c1=O
Yield: 55 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 4-phenoxybenzylamine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[CH:8][CH:7]=1.[NH:20]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=[CH:21]1>>[N:20]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[N:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1=CC=CNC=C1
Reactant: Cn1ncc(-c2ccc(OCCCCl)cc2)cc1=O
Product: Cn1ncc(-c2ccc(OCCCN3CCCCCC3)cc2)cc1=O

Procedure:
This compound was prepared as the hydrochloride salt using 5-[4-(3-chloropropoxy)-phenyl]-2-methyl-2H-pyridazin-3-one and azepine using the procedure described in Example 91 Step 5; Mp 247-8° C.; MS m/z 342 (M+H).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:15][CH:14]([NH2:16])[CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O.O>[N+:30]([C:29]1[C:24]([NH:16][CH:14]2[CH2:13][N:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=3)[CH2:15]2)=[N:25][CH:26]=[CH:27][CH:28]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CN(c2ccc3ccccc3n2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Yield: 83.3 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-amine hydrochloride (0.90 g, 3.84 mmol) in dry dimethylformamide (15 mL) was added sodium carbonate (1.22 g, 11.5 mmol) and 2-chloro-3-nitro-pyridine (608 mg, 3.84 mmol). The reaction mixture was stirred and heated at reflux for 14 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (20% to 50% ethyl acetate in petroleum ether) to give 3-nitro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyridin-2-amine (1.05 g, 3.20 mmol, 85% yield) as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[CH:27]=[N:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cnc3ccccc3n2)n1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (245 mg, 1.7 mmol) was dissolved in anhydrous DMF (10 mL), and then were added potassium carbonate (357 mg, 2.6 mmol) and 2-(bromomethyl)quinoxaline (500 mg, 2.2 mmol) in anhydrous DMF (5 mL). The mixture was stirred over a weekend at room temperature. The solvent was removed by evaporation, and the residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(quinoxalin-2-ylmethyl)sulfanyl]pyrimidin-4-ol (363 mg, 57% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 4.72 (s, 2H), 6.01 (bs, 1H), 7.81-7.88 (m, 2H), 8.03-8.11 (m, 2H), 9.10 (s, 1H); LRMS (ES+) m/z 285 (100%, M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Clc1ccc(-c2ccccn2)cn1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(-c3ccccn3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-ethylpiperazine and 6′-chloro-[2,3′]bipyridinyl.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]1>>[CH3:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:19][CH2:20]1
Reactant: CC1CCN(CCN)CC1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Product: CC1CCN(CCNc2nn3cnnc3c3c2CCCC3)CC1
Temperature: 0 °C

Procedure:
A solution of 5.0 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine in 25 ml of 1-(2-aminoethyl)-4-methylpiperidine was heated at reflux for 15 hours and then poured into ice water. The resulting off-white solid was separated by filtration and recrystallized from toluene to give 6-[2-(4-methyl-1-piperidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 180°-181° C.
Reaction SMILES: [C:1](#N)C.C1OCCOCCOCCOCCOCCOC1.CI.[OH:24][C:25]1[CH:34]=[C:33]([O:35][CH:36]([CH2:38][CH3:39])[CH3:37])[CH:32]=[C:31]2[C:26]=1[C:27](=[O:42])[CH2:28][C:29]([CH3:41])([CH3:40])[O:30]2>[Na]>[CH3:1][O:24][C:25]1[CH:34]=[C:33]([O:35][CH:36]([CH2:38][CH3:39])[CH3:37])[CH:32]=[C:31]2[C:26]=1[C:27](=[O:42])[CH2:28][C:29]([CH3:40])([CH3:41])[O:30]2
Reactant: CC#N
Reactant: CCC(C)Oc1cc(O)c2c(c1)OC(C)(C)CC2=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na]
Solvent: CI
Product: CCC(C)Oc1cc(OC)c2c(c1)OC(C)(C)CC2=O
Reaction time: 3 h
Yield: 92 %

Procedure:
In 100 ml of acetonitrile 5.6 g (20 millimoles) of the sodium salt of 5-hydroxy-7-sec. butoxy-2,2-dimethyl-4-chromanone are dissolved and stirred in the presence of 0.5 g (2 millimoles) 18-Crown-6 for 30 minutes. Thereafter 4.25 g (1.9 ml, 30 millimoles) of methyl iodide are added and the reaction mixture is stirred for another 3 hours. The inorganic salt is filtered off, the solvent removed and the residue suspended in carbon tetrachloride, extracted twice with 30 ml of water each, the organic phase is dried over sodium sulfate and evaporated. Thus 5.1 g of the desired compound are obtained in the form of a light yellow oil, yield 92%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:30])[CH3:31])=[O:9]
Reactant: CCN(c1cc(Br)cc(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid (2.0 g, 0.0058 mol) was dissolved in DMSO (20 mL) and 3-(aminomethyl)-4-isopropyl-6-methylpyridin-2(1H)-one (2.1 g, 11.7 mmol) and triethyl amine (0.585 g, 5.8 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PyBOP (4.5 g, 8.7 mmol) was added to it and stirring was continued for overnight. After completion of the reaction, the reaction mixture was poured into ice, extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to obtain crude; which then purified by solvent washings to afford the title compound (2.0 g, 68.9%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:9]12[C:15](=O)[O:14][C:12](=[O:13])[C@@H:10]1[CH2:11]2>>[CH2:1]([N:8]1[C:12](=[O:13])[CH:10]2[CH:9]([CH2:11]2)[C:15]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)[C@@H]2C[C@H]12
Product: O=C1C2CC2C(=O)N1Cc1ccccc1
Temperature: 180 °C

Procedure:
63.2 g (0.486 mol) of 1 was added in portions to 150 ml of thionyl chloride. The mixture was refluxed for 1 hour, then was stripped. The residue was distilled to give cis-1,2-cyclopropanedicarboxylic acid anhydride (3A) bp 134° C. (10 Torr.). 2.14 g (0.02 mol) of benzylamine was carefully added to 2.24 g (0.02 mol) of 3A (CAUTION: THE REACTION IS VERY EXOTHERMIC.) The mixture was heated at 180° C. for 2 hours. After cooling, the residue was recrystallized from isopropyl alcohol to give 3-(benzyl)-3-azabicyclo(3.1.0)hexane-2,4-dione, as white needles, mp 90°-91° C. (3B). A cooled (0°) solution of 305 ml (1.09 mol) of 70% sodium bis(2-methoxyethoxy)aluminum hydride in benzene diluted with 600 ml of ether was treated with 48.7 g (0.24 mole) of 3B. The mixture was stirred at 0° for 1/2 hr and refluxed for 3 hrs. After standing at room temperature overnight, excess metal hydride was destroyed by cautiously adding cold water. The mixture was filtered after addition of diatomaceous silica (Celite). The ether layer was removed and the aqueous layer was extracted with ether. The combined organic layers were dried (MgSO4). Ether and 2-methoxyethanol were evaporated under reduced pressure to give 3, as an oil. Distillation gave 3, bp: 79°-80° C. (0.01 Torr.).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH:21]1([C:27]([Cl:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[ClH:29].[CH:21]1([C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)C1CCCCC1
Yield: 68.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.66 ml (4.96 mmol) of cyclohexanoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 890 mg of the desired compound (free base) (77.0%, colorless prisms), mp: 93.0°-94.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([O:17][CH3:18])[C:4]=1/[CH:19]=[CH:20]/[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:4]2[C:5]([O:17][CH3:18])=[CH:6][C:7]3[C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][C:11]([CH3:13])([CH3:14])[C:12]=3[C:3]=2[O:2][CH3:1])=[CH:28][CH:27]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c(OC)c1/C=C/c1ccc(CO)cc1)C(C)(C)CCC2(C)C
Solvent: c1ccncc1
Product: COc1cc2c(c(OC)c1/C=C/c1ccc(COC(C)=O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.7 millimoles) of the benzyl alcohol derivative from Example 27 was dissolved in 5 ml of pyridine, and 1 ml of acetic anhydride was added. The mixture was stirred overnight at room temperature, after which ice/water was added and the resulting solid was filtered off under suction, washed with water, with 0.5N HCl and again with water and dried to give 1 g of the title compound of melting point 73°-74° C.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:18][C:19](=[O:25])[NH:20][C@@H:21]([CH3:24])[CH:22]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19](=[O:25])[NH:20][C@@H:21]([CH3:24])[CH:22]=[CH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C[C@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Methyltriphenylphosphonium bromide (16.92 g, 47.30 mmol) was taken up in toluene (350 mL). The heterogeneous solution was cooled to 0° C. then KHMDS 0.5M in toluene (90 mL, 45 mmol) was added. The reaction was stirred at 0° C. for 30 min, then cooled to −78° C. and (1-(S)-methyl-2-oxo-ethyl)-carbamic acid benzyl ester (6.11 g, 29.56 mmol) that was dissolved in toluene (45 mL) was added. The solution was warm to rt, stirred at it for 30 min, then quenched with sat NH4Cl(aq) (150 mL). The layers were separated and the aqueous was washed with EtOAc. The organics were combined and dried over Na2SO4. Solids were removed by filtration and solvent removed under reduced pressure. (1-(S)-methyl-allyl)-carbamic acid benzyl ester (4.90 g, 81%) was isolated by silica gel chromatography as a colorless oil.