Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[S:12])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](C)(C)[O-].[K+].C(OCC)(=O)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[S:12])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
To 57 mg of ethyl 5-chloro-3-phenylthioindole-2-carboxylate from Preparation 5 in 1.7 mL of dry tetrahydrofuran, under argon, was added 48 mg of solid potassium trimethylsilanolate. The resultant mixture was stirred at room temperature for 20 h. Ethyl acetate and 1 N HCl were then added. The organic layer was washed with brine (2×) and dried over MgSO4. Filtration and concentration gave a yellow gum which was triturated with ether-hexane to give the title compound. 1H NMR (250 MHz, CDCl3) δ 7.09-7.18 (m, 3H), 7.20-7.25 (m, 2H), 7.30 (dd, 1H, J =8.6 and 2.0 Hz), 7.43 (d, 1H, J =2.0 Hz), 7.52 (d, 1H, J =8.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[O:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[C:53]([NH:55][NH2:56])=[O:54]>CN(C)C1C=CN=CC=1.ClCCl>[O:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[C:53]([NH:55][NH:56][C:18](=[O:19])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:17][CH:16]=1)=[O:54]
Reactant: NNC(=O)c1ccco1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)c1ccco1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 57.9 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 2-furanhydrazide (29 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 7.5 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was then washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure. The solid thus obtained was recrystallized from dichloromethane-hexane to give the title compound (58 mg, 0.11 mmol, 58%) as a white powder.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9].Cl[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:18]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: O=C(c1cccs1)N1CCC(O)CC1
Reactant: Clc1cccc2nccn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccs1)N1CCC(Oc2cccc3nccn23)CC1
Yield: 4.6 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.40 g, 10 mmoles) in dimethylformamide (30 ml) was added 1-(2-thienylcarbonyl)-4-hydroxypiperidine (2.11 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (1.53 g, 10 mmoles) with stirring under ice-cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate and dried. After the solvent was distilled off, the residue was purified with column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)→ethyl acetate/ethanol (50:1)] to obtain 0.15 g of the desired product (4.6%, pale yellow oily product).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][OH:14])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[C:1]([O:9][C:10]1([CH2:13][O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1(CO)CC1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a mixture of 1-(hydroxymethyl)cyclopropyl benzoate (500 mg, 2.6 mmol) and TEA (394 mg, 3.9 mmol, Shantou Xilong chemical factory) in 50 mL of dry CH2Cl2, was added MsCl (357 mg, 3.12 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe at rt. After stirring for 2 hrs at rt, the mixture was diluted with icewater and extracted with CH2Cl2 (30 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the title compound as pale yellow solid (590 mg, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc2ccccc2c1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)ccc2ccccc12
Reaction time: 8 h

Procedure:
2-hydroxynaphthalene (1 g.) is dissolved in boiling acetic acid (30 ml.), and when the solution temperature reaches 45'C, a molecular equivalent amount of concentrated nitric acid is slowly added. After standing overnight at room temperature, the reaction mixture is mixed with water. The precipitated solids are filtered, washed with water, and purified by chromatography on alumina, to yield 1-nitro-2-hydroxynaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(Cl)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(Cl)cc1)OCC

Procedure:
A solution of 8.0 g of ethyl 2-(4-chlorophenyl)-3-nitropropyl-(diethoxymethyl)phosphinate in 70 ml of ethanol is added to 64 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-chlorophenyl)propyl-(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.2 and 44.1 ppm (CDCl3).
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:5][S:6][CH:7]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[CH3:19][N:20]=[C:21]=[S:22]>C(O)C>[CH3:19][NH:20][C:21]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[C:3]([Br:2])=[CH:7][S:6][N:5]=1)=[S:22]
Reactant: NCCSCc1nscc1Br
Reactant: CN=C=S
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CNC(=S)NCCSCc1nscc1Br
Yield: 108.8 %

Procedure:
The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) with cysteamine (from cysteamine hydrochloride (3.76 g.)) was performed under conditions similar to those described in Example 122. From the reaction there was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide, which, following recrystallisation from ethanol-ether and acetonitrile, gave needles (4.05 g.), m.p. 111°-112°. The amine base (2.73 g.) was isolated by basification with sodium hydroxide and extraction with chloroform and then dissolved in ethanol and treated with methyl isothiocyanate (0.78 g.). The solution was heated under reflux for 30 minutes, concentrated and the residue triturated with ether to yield the crystalline thiourea (2.9 g.) m.p. 60°-61°. Recrystallisation from isopropyl acetate gave N-methyl-N'-[2-((4-bromo-3-isothiazolyl)-methylthio)ethyl]thiourea (2.3 g.) as needles, m.p. 62°-63°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)COc1ccc(Cl)cc1

Procedure:
A 12.8 g quantity of p-chlorophenol, 13.4 g of 1-chloro-3,3-dimethyl-2-butanone, 13.8 g of anhydrous potassium carbonate and 100 ml of acetonitrile were placed into a 200-ml egg plant type flask and refluxed for 8 hours. The resulting potassium chloride was filtered off from the reaction mixture, and the filtrate was concentrated in a vacuum to obtain crude crystals, which were recrystallized from n-hexane, giving 16.0 g of the above-identified desired compound, m.p. 62°-63° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH2:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.101 g, 0.178 mmol) and 2-aminoethyl-methyl-sulfone (0.30 g, 2.436 mmol) the title compound was obtained as a yellow solid (72 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 7.93 (d, J=5.3 Hz, 1H), 7.62-7.75 (m, 1H), 7.36-7.51 (m, 1H), 7.17-7.36 (m, 5H), 5.72 (d, J=5.3 Hz, 1H), 3.71 (t, J=4.6 Hz, 4H), 3.59-3.68 (m, 2H), 3.46 (t, J=4.6 Hz, 4H), 3.34 (s, 2H), 3.02 (s, 3H). MS (ESI): 655.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 337 g of 4-nitro-3-(4-chlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(4-chlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.[S:18]1[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[N:19]1>CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:24][C:20]3=[N:19][S:18][N:22]=[C:21]3[N:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nsnc1N
Reactant: O=C(C(=O)c1cccc(F)c1)c1ccncc1
Solvent: CC(=O)O
Product: Fc1cccc(-c2nc3nsnc3nc2-c2ccncc2)c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of 1-(3-fluorophenyl)-2-pyridin-4-ylethane-1,2-dione (1.5 g, 6.5 mmol) and 1,2,5-thiadiazole-3,4-diamine (1.1 g, 9.8 mmol) in AcOH (30 mL) was stirred and heated at reflux for 1 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and a solution of NaHCO3 4%. The organic phase was dried (MgSO4) and evaporated to dryness to give the title compound as a dark oil (1.7 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Br)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1Br)C2
Yield: 74.2 %

Procedure:
A mixture of 7-(2-bromophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.49 g), aminoguanidine hydrochloride (0.19 g), concentrated hydrochloric acid (0.39 ml), water (0.39 ml) and ethanol (50 ml) was refluxed for 6.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 7-(2-bromophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 66) (0.47 g) as colorless crystals.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].N12CCCN=C1CCCCC2.[CH:29]([C:31]([CH3:33])=[O:32])=[CH2:30]>O1CCCC1>[CH2:1]([C:5]1([CH2:30][CH2:29][C:31](=[O:32])[CH3:33])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(C)=O
Reactant: CCCCC1CCc2cc(OC)ccc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCC1(CCC(C)=O)CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (230 mg, 1 mmol) in anhydrous tetrahydrofuran (THF, 0.5 mL) was placed under a N2 atmosphere and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.037 mL, 0.25 mmol) followed by methyl vinyl ketone (MVK, 0.104 mL, 1.25 mmol). The mixture was stirred at room temperature for 19 hours and then heated at 60° C. for 80 minutes. Additional MVK (0.104 mL, 1.25 mmol) was added and the mixture was stirred at 60° C. for 2.5 hours. Additional DBU (0.037 mL, 0.25 mmol) was then added and the mixture was stirred at 60° C. for 70 minutes. After cooling to room temperature, the mixture was concentrated under a stream of N2 and the residue was purified by preparative layer chromatography on three 0.1×20×20 cm silica gel GF plates (Analtech, Newark, Del.), developing with 5% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 2-butyl-6-methoxy-2-(3-oxobutyl)-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH3:10])([CH2:7]O)[C:3]([O:5][CH3:6])=[O:4].S(Cl)([Cl:13])=O.N1C=CC=CC=1>>[CH3:1][C:2]([CH2:9][CH3:10])([CH2:7][Cl:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)(CO)C(=O)OC
Solvent: c1ccncc1
Product: CCC(C)(CCl)C(=O)OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
The methyl 2-methyl-2-ethyl-3-hydroxypropionate was added at below 20° C. to 178.6 g (1.5 mol) of thionyl chloride, and the mixture was stirred at 50° C. for a further 30 min. Excess thionyl chloride was then distilled off at 100 mbar, 0.5 g (0.006 mol) of pyridine was added to the residue, and the mixture was heated at from 130° to 135° C. for 45 min. Fractional distillation gave 114.4 g of methyl 2-methyl-2-ethyl-3-chloropropionate having a boiling point of 101°-104° C./8 mbar, corresponding to a 93.2% yield, based on methyl 2-methyl-2-ethyl-3-hydroxypropionate. The overall yield was 69.5%, based on 2-methyl-2-ethyl-3-hydroxypropanal.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[F:40]C1C=CC=CC=1N1CCNCC1.[ClH:53]>O1CCCC1>[ClH:53].[ClH:53].[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:40])[CH2:10][CH2:9]1)=[O:7]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccccc2F)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 2.2 g (0.01 mole) of 1,1'-carbonyldiimidazole, 2.2 g (0.01 mole) of unsym-dimethylethylenediamine and 2.5 g (0.01 mole of 1-(2-fluorophenyl)piperazine in a total volume of 100 ml of tetrahydrofuran gave an oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the solid recrystallized from methanol-diethyl ether to give 2.3 g (46%) of title compound as a white solid, m.p. 153°-155° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)[CH:14]=[CH:15][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:25]([O-:30])([N+]([O-])=O)=[O:26].C(Cl)(Cl)Cl.Cl>[OH-].[Na+]>[N+:25]([C:8]1[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=3)=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:30])=[O:26]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1ccc(-c2ccc3occ(-c4ccccc4)c3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(-c2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)cc1

Procedure:
A solution of 3.1 g. (0.01 mole) of the product of step D and 2 g. of dinitrogen tetraoxide in 250 ml. of chloroform is stirred at about 20° C. for about 16 hours. Evaporation of the mixture provides a residue which is dissolved in 10 percent sodium hydroxide solution, then acidified with hydrochloric acid. The precipitate is collected by filtration, dissolved in a chloroform/ethanol mixture and chromatographed on silica gel, eluting with chloroform. The solid obtained is recrystallized twice from a mixture of water and N,N-dimethylformamide to provide yellow crystals of 4-(2-nitro-3-phenylbenzofuran-5-yl)benzoic acid, m.p. 259°-261° C.
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1>CCCCCC>[OH:10][CH:4]([CH:12]1[CH2:13][CH2:14][CH2:15][C:11]1=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: CCCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of hexanal (100 g) and cyclopentanone (152 g) was added dropwise thereto under stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and then separated. The resulting organic layer was further washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a crude product (188 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 142 g of 2-(1-hydroxyhexyl)cyclopentanone (boiling point: 107-108° C./666 Pa; GC purity: 94%). The remaining 6% was 2-hexylidenecyclopentanone which is a dehydration product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[I:11].C([N:15]([CH:18]([CH3:20])[CH3:19])CC)(C)C.C1(N)CC1>S(Cl)(Cl)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:18]2[CH2:20][CH2:19]2)=[O:8])=[CH:4][C:3]=1[I:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Agent: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodobenzoic acid (9.00 g, 31.9 mmol) was heated to 75° C. in thionyl chloride (15 mL) for 4 h. The reaction mixture became homogeneous and was concentrated and dried azeotropically with toluene. The mixture was dissolved in 1,4-dioxane (10 mL), and diisopropylethylamine (11 mL mL, 64 mmol), and cyclopropylamine (2.45 mL, 35 mmol) and stirred at ambient temperature for about 2 h. The reaction was diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with 3 N HCl (aqueous). The organic layers were combined, washed 2 times with 50 mL of 3 N HCl (aqueous), and 2 times with 50 mL of sodium bicarbonate, dried over sodium sulfate, and concentrated via rotovap to give the title compound. Found MS (ES+): 322(M+H)+.
Reaction SMILES: Br[CH:2]1[C:12](=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1.[C-:14]#[N:15].[Na+].O.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C1(C)C=CC=CC=1>[C:14]([CH:2]1[C:12](=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1)#[N:15]
Reactant: O=C1C2=C(C=CC1Br)CCCCC2
Reactant: [C-]#N
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1C=CC2=C(CCCCC2)C1=O
Temperature: 90 °C
Reaction time: 15 h

Procedure:
2-cyanobenzocycloheptan-1-one (compound Ia) was prepared by dissolving 2-bromobenzocycloheptan-1-one (30.2 g, 0.126 mol) in toluene (150 mL) in a 500 mL round bottom flask equipped with a condenser. NaCN (18.6g, 0.38 mol), water (50 g), and dibenzo-18-crown-6 (0.5 g) were added to the flask. The reaction mixture was stirred vigorously at 90° C. under a static blanket of nitrogen for 15 hours. The reaction mixture was cooled and washed three times with water (70 mL×2+100 mL). The toluene solution was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was distilled under vacuum to give a yellow liquid (21.1 g, b.p. 158-162° C. at 17 mm Hg). The purity of the liquid was 96% by GC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
4-(Benzyloxy)phenol (2.89 g, 0.01443 mol) in dimethylformamide (15 ml) and 2-(dimethylamino)ethyl chloride hydrochloride (2.32 g, 0.01611 mol) were added simultaneously in small portions to a 55-65% sodium hydride dispersion in mineral oil (0.033 mol) in dimethylformamide (5 ml) at 0° C. Then the mixture was allowed to warm to 90° C., and stirring was continued for 1.5 h. The cooled mixture was poured into water. The resultant mixture was extracted with toluene. The combined extracts were washed with 2.5 M NaOH and water and dried over Na2SO4. Toluene was evaporated and the residual product was used as such in the next step.