Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].[CH2:21]=O.Cl.[CH3:24][NH:25][CH3:26]>C(O)C>[CH3:24][N:25]([CH2:21][C:5]1[O:1][C:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:3][CH:4]=1)[CH3:26]
Reactant: CNC
Reactant: C=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccco1
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccc(CCCCN2C(=O)c3ccccc3C2=O)o1
Reaction time: 20 h
Yield: 49.8 %

Procedure:
2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3(2H)-dione (5.38 g), paraformaldehyde (1.2 g) and dimethylamine hydrochloride (3.26 g) were refluxed in absolute ethanol (100 ml). After 6 hr further paraformaldehyde (0.6 g) and dimethylamine hydrochloride (1.6 g) were added and heating continued for a further 20 hr. The solvent was removed, the residue made strongly basic with 5 N sodium hydroxide, extracted with ethyl acetate and the organic layer evaporated. The crude product was purified by column chromatography to give an amber oil (3.25 g) Rf 0.4 silica/methanol. NMR (CDCl3) 8-8.6 m (4H); 7.75 s (6H); 7.3 m (2H); 6.55 s (2H); 6.3 m (2H); 4.0 m (2H); 1.9-2.4 m (4H).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:12]1
Reactant: CN1CCCC(O)C1
Reactant: N#Cc1cccnc1F
Product: CN1CCCC(Oc2ncccc2C#N)C1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 1-methyl-piperidin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 218 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)=S)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]=[C:18]=[N:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[CH2:12][CH2:13]1
Reactant: S=C(NCCCN1CCN(c2ccccc2Cl)CC1)Nc1ccc2c(c1)OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccccc1N1CCN(CCCN=C=Nc2ccc3c(c2)OCCO3)CC1
Temperature: 400 °C
Yield: 56.5 %

Procedure:
A mixture of N-3-[4-(2-chlorophenyl)piperazin-1-yl]propyl-N '-(3,4-ethylenedioxyphenyl)thiourea of Example 11 (1.35 g; 3 mmol), triphenylphosphin (1.02 g; 3.9 mmol), carbon tetrachloride (0.56 ml), triethylamine (0.3 g; 3 mmol) and methylene chloride (15 ml) Was stirred at reflux for 3 h and at 400° C. for 16 h. The reaction mixture was concentrated in vacuo and then taken up in petroleum ether. The solution was filtered and concentrated in vacuo to give 0.7 g N-3-[4-(2-chlorophenyl)piperazin-1-yl]propyl-N'-(3,4-ethylenedioxyphenyl)carbodiimide as an oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])/[C:3](/O)=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23](=[O:28])/[CH:24]=[C:25](\[NH2:27])/[CH3:26])[CH3:21]>C(#N)C>[CH2:20]([O:22][C:23](=[O:28])[C:24]1[C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:27][C:25]=1[CH3:26])[CH3:21]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 34.1 %

Procedure:
To an acetonitrile (50 ml) solution of (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethyl-phenyl)-but-2-en-1-one (4.7 g, 17 mmol; D. Barrett, P. D. Bentley, T. R. Perrior, Synthetic Commun. 1996, 26, 3401–3406) was added ethyl-3-aminocrotonate (4.27 g, 33 mmol) under an argon atmosphere. The mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/ethyl acetate) to yield 2.2 g (5.8 mmol, 35%) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][C:18]([OH:22])([CH3:21])[CH2:17][CH2:16]1)[C:4]1[C:5]([CH3:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[H-].[Na+].[CH3:25]I>C1COCC1>[CH2:1]([N:3]([CH:15]1[CH2:16][CH2:17][C:18]([O:22][CH3:25])([CH3:21])[CH2:19][CH2:20]1)[C:4]1[C:5]([CH3:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: CI
Reactant: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a cooled solution of methyl 3-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)-2-methylbenzoate (300 mg, 0.98 mmol) in THF (5 ml), was added sodium hydride (235 mg, 5.89 mmol) portion-wise followed by methyl iodide (0.61 ml, 9.8 mmol). The mixture was stirred at room temperature for 1 h, cooled to 0° C. quenched with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 300 mg of the crude title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C[Sn](C)(C)[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][N:36]=1)[C:32]#[N:33]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][N:36]=3)[C:32]#[N:33])[CH:7]=[CH:6][CH:5]=2)([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[N:9]=1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Reactant: C[Sn](C)(C)c1cc(C#N)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(C2(c3cccc(-c4cc(C#N)ccn4)c3)N=C(N)c3c(F)cccc32)ccn1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 8.4 %

Procedure:
1-(3-Bromophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (0.200 g, 0.49 mmol), 2-(trimethylstannyl)isonicotinonitrile (0.194 g, 0.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.056 g, 0.05 mmol) and DMF (4 mL) were put in a microwave vial and heated in a microwave reactor at 110° C. for 20 min, then at 150° C. for 20 min. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate. The aqueous layer was extracted with EtOAc (×2), the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.018 g, 9%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.86 (dd, 1 H) 8.40 (t, 1 H) 8.11-8.15 (m, 1 H) 8.04 (d, 1 H) 8.01 (ddd, 1 H) 7.78-7.81 (m, 1 H) 7.66 (d, 1 H) 7.51-7.57 (m, 1 H) 7.42-7.47 (m, 2 H) 7.24-7.31 (m, 1 H) 6.88 (dd, 1 H) 6.59-6.71 (m, 3 H) 3.79 (s, 3 H); MS (ES+) m/z 436 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:30]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccccc2Cl)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (51.4 mg, 0.187 mmol) in CH2Cl, (2 mL) was added 2-chlorophenyl isocyanate (0.25 μL, 0.207 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 140 as a colorless solid (76.5 mg, 95%). LCMS m/z (%)=428 (M+H35Cl, 100), 430 (M+H37Cl, 37) 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (bs, 1H), 8.25 (bs, 1H), 8.15 (dd, J=8.33, 1.48 Hz, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=2.70 Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, J=8.92 Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, J=1.84 Hz, 1H), 3.98 (t, J=6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][OH:27].[CH2:29]([O:36][C:37]1[CH:38]=[C:39](O)[CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[CH:42]=[C:41]([CH:40]=[CH:39][CH:38]=1)[O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)CCO
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: CN(C)CCOc1cccc(OCc2ccccc2)c1

Procedure:
Compound 113A was prepared in a similar manner to the synthesis of step 1 of Example 35 by substituting compound 34D and compound 31F with 2-(dimethylamino)ethanol and 3-(benzyloxy)phenol, respectively: DCI (+)MS: 272 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][S:38]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccccc1)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of α-toluenesulfonylchloride (143 mg, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 69%). 1H NMR (400 MHz, CDCl3) δ7.27-7.22 (m, 3H), 7.16-7.14 (m, 2H), 7.07 (d, 2H), 6.83 (d, 2H), 4.05 (s, 2H), 3.95 (t, 2H), 3.68-3.63 (m, 2H), 3.55 (t, 1H), 3.49-3.44 (m, 2H), 3.01 (d, 2H), 2.57 (t, 2H), 2.47 (s, 4H), 2.02-1.93 (m, 4H), 1.78-1.72 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[CH:40]=[CH:39][N:38](C3CCCCO3)[N:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[NH:37][N:38]=[CH:39][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccn(C4CCCCO4)n3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1F
Yield: 99.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide (281 mg, 0.418 mmol) prepared in Example 150a, triethylsilane (0.60 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield the title compound (182 mg, 99%) as a colorless solid.
Reaction SMILES: [C@H:1]12[C:10](=O)[O:9][C:7](=[O:8])[C@H:3]([CH2:4][CH2:5][CH2:6]1)[CH2:2]2.[CH:12]([O:19]CC)([O:16][CH2:17][CH3:18])OCC.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C@H:5]1([C:12]([O:16][CH2:17][CH3:18])=[O:19])[CH2:6][CH2:1][CH2:2][C@@H:3]([C:7]([O:9][CH2:10][CH3:22])=[O:8])[CH2:4]1
Reactant: CCOC(OCC)OCC
Reactant: O=C1OC(=O)[C@H]2CCC[C@@H]1C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCC[C@H](C(=O)OCC)C1
Temperature: 60 °C

Procedure:
Anhydride 1 (7.71 g; 50 mmol) was combined with triethyl orthoformate (12.5 mL; 75 mmol; 1.5 equiv) and ethanol (50 mL). p-Toluenesulfonic acid (0.48 g; 2.5 mmol; 0.05 equiv) was added and the reaction mixture was heated overnight at 60° C. to completely consume 1. Solid sodium bicarbonate (0.5 g) was added and the solvent was removed at reduced pressure. The residue was dissolved in toluene (25 mL), washed with saturated aqueous NaHCO3 (5 mL), dried over Na2SO4, and concentrated to afford 11.42 g (99%) of cis-2b which was a single peak by GC analysis.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:1][C:2]1[O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10](=[O:12])[CH:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: Nc1cc(=O)c2ccccc2o1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc(=O)c2ccccc2o1)C(=O)OCC
Temperature: 130 °C
Yield: 90.7 %

Procedure:
A mixture of 2-aminochromone (3.22 g, 0.02 mole) and diethyl ethoxymethylenemalonate (8.64 g, 0.04 mole) is heated at 130° C. under nitrogen until an homogeneous solution forms (16 hrs.). The reaction mixture is cooled. The product, which precipitated, is filtered off and washed with hexane. Recrystallization from ethylacetate gives pale yellow crystals (6.01 g, 91%), mp 138°-140° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].[Ag:15]>CC(C)=O>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10].[Ag+:15]
Reactant: [Ag]
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)(C)CCCCCC(=O)[O-]
Product: [Ag+]

Procedure:
To a reaction flask equipped with a mechanical stirrer, thermometer was charged 12.0 g (0.070 mole) of neodecanoic acid, 60 g of 0.1N sodium hydroxide. Silver foil was used as the anode and a graphite rod as the cathode. After passing 5,590 coulombs of direct current, 3.47 g (0.032 mole) of silver was consumed. A black sticky material was obtained after removal of the aqueous phase. This material was tertiurated with acetone and gave a black crystalline solid containing 25.0% silver. From the acetone was obtained a white solid containing 28.0% silver.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(S(=O)(=O)N2CCOCC2)cc1)C(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.22 g), 2-[4-(morpholine-4-sulfonyl)benzyl]-3-oxopentanoic acid methyl ester (0.41 g), polyphosphoric acid (1 g) and dioxane (20 mL) was heated at 130° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate, dichloromethane and methanol (1:4:0 to 1:1:0 to 0:9:1 by volume) to afford title compound, 0.14 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:44].[N:45]1([CH2:51][CH2:52][C:53](O)=[O:54])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.Cl>CCOCC.C(Cl)Cl>[ClH:44].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:53](=[O:54])[CH2:52][CH2:51][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.12 g. (8.2 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-p-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c] [1]benzopyran, prepared according to the method of Example 6, 1.77 g. (8.6 mmoles) of dicyclohexylcarbodiimide and 1.65 g. (8.5 mmoles) of β-piperidinopropionic acid hydrochloride (m.p. 216° - 220°, J. Am. Chem. Soc. 73, 3168 (1951) are combined with 125 ml. of methylene chloride and stirred at room temperature for about 20 hours. The reaction mixture is filtered and the methylene chloride removed using a rotary evaporator. The residue is treated with benzene and filtered to remove a small quantity of insoluble material. The benzene is evaporated and the dark, viscous residue is chromatographed using 100 g. of 60 - 100 mesh Florosil activated magnesium silicate and methanol/chloroform graded solvent mixtures. Chromatography yields an oil which is dissolved in ether and treated with a solution of ethereal HCl. The desired compound appears as crystals which are filtered and washed with additional ether to obtain the desired product.
Reaction SMILES: [CH3:1]C1CCCCC1=O.CC1CCCC1=O.[CH3:16][O:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>>[CH3:16][O:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][CH2:1][C:22]1=[O:26]
Reactant: COC(=O)CCC1(C)CCCC1=O
Reactant: CC1CCCCC1=O
Agent: CC1CCCC1=O
Product: COC(=O)CCC1(C)CCCCC1=O

Procedure:
In the same manner but replacing 2-methylcyclohexanone with an equivalent amount of 2-methylcyclopentanone, 1-methyl-2-oxocyclopentanepropionic acid methyl ester, bp 88°-100° C./1.1 mm, nmr (CDCl3) δ 1.0 (s, 3H), 1.8 (m, 6H), 2.3 (m, 4H), 3.7 (s, 3H), is obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C:16](=O)[CH2:15][N:14]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:12]=2[CH:26]=1.P(Cl)(OCC)(OCC)=O.[N+:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])#[C-:37]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[CH:37]=[N:36][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:16]3[CH2:15][N:14]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:12]=2[CH:26]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Reaction time: 0.08 h

Procedure:
Potassium t-butoxide, 1.29 g (0.0115 mol) was added to a stirred solution of 2.88 g (0.01 mol) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 50 ml of tetrahydrofuran, that had been cooled in an ice bath and covered with a nitrogen atmosphere. After stirring for 5 minutes, 2.59 g (0.015 mol) diethyl chlorophosphate was added. After stirring for 5 minutes, a mixture of 2.26 g (0.02 mol) of ethyl isocyanoacetate in 50 ml of tetrahydrofuran that had been treated with 2.24 g (0.02 mol) of potassium t-butoxide just prior to the addition, was added. After 5 minutes, the ice bath was removed and the stirring was continued for 15 minutes. The mixture was acidified with 2 ml of glacial acetic acid, diluted with 200 ml of saturated sodium bicarbonate solution and extracted twice with 125 ml portions of toluene. The extracts were dried and evaporated and the residue was crystallized from ether to give the product with mp 195°-197°. For analysis, the material was recrystallized from methylene chloride/ether/hexane to give colorless crystals with mp 195°-196°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21]CCCCC=C>>[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]
Reactant: C=CCCCCNC
Reactant: C=CCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC=CCCCCNC

Procedure:
N-Methylhept-5-en-1-amine tosylate salt 31b was synthesized from 7-bromo-heptene, according to the procedure as described for compound 31a, as a white solid in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ 1.38 (q, J=7.76 Hz, 2H), 1.71 (q, J=7.76 Hz, 2H), 1.80 (q, J=6.98 Hz, 2H), 1.99 (q, J=6.98 Hz, 2H), 2.38 (s, 3H), 2.70 (t, J=5.17 Hz, 3H), 2.87-2.93 (m, 2H), 4.92-4.99 (m, 2H), 5.67-5.73 (m, 1H), 7.20 (d, J=7.76 Hz, 2H), 7.75 (d, J=7.76 Hz, 2H), 8.62 (br s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[C:12]1([CH:18]2[NH:22][C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][S:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>CCOCC.O>[C:12]1([CH:18]2[N:22]([C:27]([O:29][CH3:30])=[O:28])[C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][S:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)Cl
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2)N1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)N1C(c2ccccc2)SC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a mixture of 60 g. of sodium carbonate in 330 ml. of water and 220 ml. of 10% sodium bicarbonate was added 62.7 g. (0.3 mole) of 2-phenyl-4-(R)-carboxythiazolidine. A solution of 23.0 ml. (28.4 g., .3 mole) of methyl chloroformate in 75 ml. of ether was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for one additional hour. The entire reaction mixture, including some solid which occasionally separated, was acidified carefully (foaming) to pH 1 by the dropwise addition of about 50 ml. of 6N HCl. The reaction was extracted 3 × 300 ml. portions of methylene chloride. The organic phases were dried over sodium sulfate and evaporated to afford 77.4 g (97%) of the 2-phenyl-3-carbomethoxy-4-(R)-carboxythiazolidine as a white crystalline solid, having a m.p. of 129°-130° C.