Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:32][C:29]2[CH:30]=[N:31][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:2][CH2:3]5)(=[O:6])=[O:5])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)=[CH:27][CH:28]=2)[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in 1,2-dichloroethane (5 mL) was added 1-acetylpiperazine (65 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (140 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (114 mg, yield 92%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (19:1, volume ratio). MS: 577 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=O)[CH2:12][CH2:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:9])=[CH:4][CH:3]=1.C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[OH:21])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)CCC(=O)c1ccccc1)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: C[C@H](NCCCC(O)c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
A 250-mL RBF equipped with a magnetic stirbar was charged with solid (S)—N-(1-(4-bromophenyl)ethyl)-4-oxo-4-phenylbutanamide (2.85 g, 7.9 mmol) and placed in an ice bath. To the stirred solid was added 1.0 M BH3 in THF (30 mL, 30 mmol). The ice bath was removed and the mixture was stirred at rt for 2.5 h. The mixture was poured into 5% aq HCl (100 mL) and concentrated under reduced pressure to remove the THF. The aqueous residue was basified to pH 14 by portionwise addition of NaOH pellets. The mixture was extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 extracts were dried over Na2SO4. Removal of the solvent afforded crude 4-((S)-1-(4-bromophenyl)ethylamino)-1-phenylbutan-1-ol (2.58° g, 94%) as an oil. LC-MS Method 1 tR=1.20 min, m/z=348, 350.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].O.Cl>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])#[N:2]
Reactant: O=C(N(CCCCBr)c1ccc(O)cc1)C(F)(F)F
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCN(C(=O)C(F)(F)F)c1ccc(O)cc1
Temperature: 64 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Sodium cyanide (17.2 g, 0.35 mol) was stirred mechanically in 325 mL DMSO under nitrogen and heated to 64° C. The 29.7 g of N-(4-bromobutyl)-N-(4-hydroxyphenyl)trifluoroacetamide in 125 mL of DMSO was dripped in over 13/4 hours. The reaction was stirred for two hours at 65°-72° C., cooled to -15° C., and poured into 3 L of ice and water. The cold mixture was immediately acidified with about 350 mL of 1N HCl and extracted three times with a total of 1.2 L of ethyl acetate. The ethyl acetate extracts were washed once with saturated sodium chloride solution and dried over magnesium sulfate. The solution was evaporated on a rotary evaporator to yield 11.5 g of N-(4-cyanobutyl)-N-(4-hydroxyphenyl)trifluoroacetamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([Cl:15])[CH:3]=1.C(O)C.[OH-].[Na+]>O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([Cl:15])[CH:3]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To the ethyl (4-amino-2,5-dichlorophenyl)acetate (14) (4.36 g, 17.57 mmol) were added ethanol (30 ml) and 1N NaOH (35 ml), and the mixture was stirred at room temperature for 1 hour. After adding water (30 ml) to the reaction mixture, the reaction mixture was concentrated to about half the volume under reduced pressure. To this concentrate, 1N HCl (36 ml) was added under cooling, and the precipitated crystals were collected by filtration under reduced pressure. After washing the crystals with water, the crystals were air-dried. The resulting crude crystals were dissolved in ethyl acetate:chloroform:methanol (5:5:2, v/v/v, 120 ml), and the solution was filtered under reduced pressure. The filtrate was concentrated under pressure. The precipitated crystals were washed with hexane, and dried under reduced pressure to give (4-amino-2,5-dichlorophenyl)acetic acid (20) (3.69 g, 96%) as fine prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]2[CH:10]([CH:11]=1)[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:3]1[C:2]([F:1])=[CH:11][CH:10]2[CH:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCC2C=CC(F)=CC2N1
Product: O=C1CCC2C=C(Br)C(F)=CC2N1

Procedure:
This intermediate was obtained according to general procedure I from 7-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (92 mg, 0.56 mmol) and NBS (104 mg, 0.58 mmol) after flash chromatography on silica gel (hexanes/ethyl acetate, 5/1, Rf=0.27) as white solid (120 mg, 0.49 mmol, 88%).
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>C1COCC1>[CH3:12][O:13][CH2:14][CH2:15][NH:16][S:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
Phenylmethanesulfonyl chloride (3.0 g, 15.7 mmol) was dissolved in dry THF (15 mL) and it was added dropwise to a solution of 2-methoxyethylamine (2.36 g, 31.5 mmol) in dry THF (50 mL) at 0° C. After addition the ice-bath was removed and the reaction was stirred at rt for 2.5 h. The solvent was removed in vacuo and the residue was dissolved in DCM. The mixture was washed with one portion of 5% aqueous HCl, several portions of water, dried through a phase separator and evaporated to give the title compound (3.58 g, 94%); 1H NMR (400 MHz, CDCl3): δ 7.43-7.35 (m, 5H), 4.52 (br s, 1H), 4.26 (s, 2H), 3.40 (t, 2H), 3.32 (s, 3H), 3.14-3.09 (m, 2H); Mass Spectrum: M−H+ 228.
Reaction SMILES: [CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][OH:24])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:25](Br)[C:26]#[CH:27]>>[CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:27][C:26]#[CH:25])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCBr
Reactant: CCCCCCCCc1nc2cnc3ccccc3c2n1CCO
Product: C#CCOCCn1c(CCCCCCCC)nc2cnc3ccccc3c21
Yield: 90.3 %

Procedure:
Using the general method of Example 1 Part A, 2-(2-octyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (4.8 g, 14.75 mmol) was reacted with propargyl bromide (80% in toluene, 4.93 mL, 44.25 mmol) to provide 4.84 g of 2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a brown solid.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH3:9]>>[CH2:8]([C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: O=C(O)C1CCC1
Reactant: CCBr
Product: CCC1(C(=O)O)CCC1

Procedure:
The title compound was prepared according to the procedure described for intermediate 2.1 from cyclobutanecarboxylic acid and ethylbromide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:32])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[C:26]([Cl:31])[CH:27]=[CH:28]2)[CH2:24][CH2:23][CH2:22][N:21]3[CH:20]=1)=O>>[Cl:31][C:26]1[CH:27]=[CH:28][C:29]2[C:19]([C:17]3[C:16](=[O:32])[NH:13][C:11](=[O:12])[C:10]=3[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[CH:20][N:21]3[C:30]=2[C:25]=1[CH2:24][CH2:23][CH2:22]3
Reactant: COC(=O)C(=O)c1cn2c3c(c(Cl)ccc13)CCC2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: O=C1NC(=O)C(c2cn3c4c(c(Cl)ccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
Beginning with indole-3-acetamide and (7-chloro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1)[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:3]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[CH:23][CH:24]=1)[CH3:2]
Reactant: CCN(CCc1ccccn1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CCc1ccccn1)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 20.8 %

Procedure:
Methyl 2-[(4-{3-[ethyl(2-pyridin-2-ylethyl)amino]-3-oxopropyl}phenoxy)methyl]-benzoate (0.135 g, 0.30 mmol) was dissolved in a mixture of THF/water (7/1, 5 ml) and lithium hydroxide (29 mg, 1.2 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation. The crude product was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 27 mg of 2-[(4-{3-[ethyl(2-pyridin-2-ylethyl)amino]-3-oxopropyl}phenoxy)methyl]benzoic acid (yield 20.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42]>>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: COC(=O)CCN
Product: COC(=O)CCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-propionic acid methyl ester.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[CH:9][C:8]([CH3:12])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:16](=O)[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>C1C=CC=CC=1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:16]([CH:13]4[CH2:14][CH2:15]4)[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]=3[C:8]([CH3:12])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C2CCCC2)n1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCC1
Reaction time: 4 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 33 using 1-cyclopentyl-3-methyl-1H-pyrazol-5-amine (570 mg, 3.45 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (635 mg, 3.45 mmol), and benzene (50 mL) wherein the reaction time was 4 h. The crude product was purified via silica gel chromatography (eluent: 0 to 10% EtOAc:Hex). The final product was collected as 0.740 g (68%). LCMS E-S (M+H)=314.3 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04-1.21 (m, 4 H) 1.47 (t, J=7.20 Hz, 3 H) 1.73 (br. s., 2 H) 2.00 (d, J=2.78 Hz, 2 H) 2.08-2.16 (m, 4 H) 2.21 (s, 1 H) 2.67 (s, 3 H) 4.49 (q, J=7.16 Hz, 2 H) 5.32 (t, J=7.83 Hz, 1 H) 7.40 (s, 1 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reactant: ClCc1ccccc1
Product: CCCN(CCC)C1CCc2c(cccc2N(Cc2ccccc2)C(C)=O)C1

Procedure:
Starting from 2.55 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 1.50 g (0.012 mol) of benzyl chloride the title compound is obtained analogously to Example 4.7.1 in the form of a gum in a yield of 3.0 g (79.0% of theory).
Reaction SMILES: C(OC([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:11])C)(=O)C(C)C.C(=O)([O-])O[C:25]1C=CC([N+]([O-])=O)=[CH:27][C:26]=1[CH:34]([O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])C>>[C:37]([O:36][CH:34]([O:11][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:9])[CH:26]([CH3:25])[CH3:27])(=[O:41])[CH:38]([CH3:39])[CH3:40]
Reactant: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Reactant: CC(C)C(=O)OC(C)c1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Product: CC(C)CC(CNC(=O)OC(OC(=O)C(C)C)C(C)C)CC(=O)O
Yield: 51 %

Procedure:
Following the procedure of preparation for (110), and substituting (114) for (111), provided the title compound as a mixture of two diastereomers in 51% yield. 1H-NMR (CDCl3, 400 MHz): δ 0.89 (m, 12H), 1.17 (m, 8H), 1.65 (m, 1H), 2.02 (m, 1H), 2.16 (m, 1H), 2.33 (m, 2H), 2.56 (m, 1H), 3.13 (m, 1H), 3.30 (m, 1H), 5.00 (m, 1H), 6.57-6.56 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F>[Zn].N>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[CH:7]=1
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: N
Agent: [Zn]
Product: Fc1cc(Cl)c(F)nc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
55.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine (Fluorochem) and 20 g of zinc powder were added to 560 ml of 20% aqueous ammonia, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was refluxed while removing water using a Dean-Stark trap, to obtain 46.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:15]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: ClCCl
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 2-chloro-5-(chlorosulfonyl)benzoic acid (0.51 g, 2.0 mmol) was added dichloromethane (10 mL), oxalyl chloride (1.5 mL) and one small drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 3 days. The mixture was then concentrated until oxalyl chloride was gone to give 2-chloro-5-(chlorosulfonyl)benzoyl chloride. The residue was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH:29][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: NCCc1cccc(F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCc1cccc(F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 2-(3-fluoro-phenyl)ethylamine (0.051 mL, 0.389 mmol) and triethylamine (0.135 mL, 0.972 mmol) in acetonitrile (10 mL). The reaction mixture stirred for 1 hr at room temperature, concentrated and crude product purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide. LCMS m/z=412.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][CH2:18][C:19]([OH:21])=O)[S:16][CH2:15][CH2:14][CH2:13][S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:37]([NH2:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:44]([O:45][CH3:46])=[C:41]([O:42][CH3:43])[CH:40]=1>O1CCCC1>[CH3:43][O:42][C:41]1[CH:40]=[C:39]([CH:48]=[CH:47][C:44]=1[O:45][CH3:46])[CH2:38][CH2:37][NH:49][C:19](=[O:21])[CH2:18][CH2:17][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[S:12][CH2:13][CH2:14][CH2:15][S:16]1
Reactant: COc1ccc(C2(CCC(=O)O)SCCCS2)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)CCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC
Reaction time: 3 h

Procedure:
13.2 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionic acid, 4 g of triethylamine and 180 ml of tetrahydrofuran are cooled to 0° C. and treated dropwise within 10 minutes with 5.44 g of chloroformic acid isobutyl ester in 80 ml of tetrahydrofuran. The mixture is then held at room temperature for 3 hours and treated at 0° C. with 7.25 g of homoveratrylamine in 40 ml of tetrahydrofuran. The suspension is left to stand at 3° C. for 48 hours, then evaporated, treated with water and extracted with ether/methylene chloride (3:1). The ethereal extracts are washed with water, sodium bicarbonate solution, 1-N tartaric acid and water. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized from methylene chloride/ether at 0° C. There is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionamide of melting point 135°-136° C.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]([F:22])([F:21])C1C=CC(N2C3C(=CC=CC=3)CCC2)=CC=1.Cl.Cl.[CH3:25][C:26]1([CH3:49])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH:33]2[C:28](=[CH:29][C:30]([O:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[CH:31][CH2:32]2)[NH:27]1>>[ClH:42].[ClH:1].[CH3:25][C:26]1([CH3:49])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:4]([F:22])([F:21])[F:3])[CH:37]=2)[CH:33]2[C:28](=[CH:29][C:30]([O:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[CH:31][CH2:32]2)[NH:27]1
Reactant: FC(F)(F)c1ccc(N2CCCc3ccccc32)cc1
Reactant: CN(C)CCOC1=CCC2C(=C1)NC(C)(C)CC2c1ccc(Cl)cc1
Agent: Cl
Product: CN(C)CCOC1=CCC2C(=C1)NC(C)(C)CC2c1cccc(C(F)(F)F)c1

Procedure:
2,2-dimethyl-7-dimethylaminoethoxy-4-(4-trifluoromethylphenyl-tetrahydroquinoline dihydrochloride m.p. 141°-8°; and 2,2-dimethyl-7-dimethylaminoethoxy-4-(4-chlorophenyl)tetrahydroquinoline dihydrochloride m.p. 139°-143°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[N:26]([S:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:47])=[O:46])[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 70.3 %

Procedure:
To a solution of {4-[(1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.215 g, 0.51 mmol) in CH2Cl2 (10 mL) was added Et3N (0.30 mL, 2.15 mmol) followed by benzenesulfonyl chloride (0.—ml, 1.02 mmol) and the resultant solution was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (40 mL), washed with brine (3×10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (15:1 CH2Cl2-MeOH) provided 0.202 g (70%) of {4-[(1-Benzenesulfonyl-1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as an orange-brown oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]([CH3:36])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]([CH3:36])=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Cc1cc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2nc1Sc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Yield: 16 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (37 mg, 0.14 mmol), potassium carbonate (158 mg, 1.14 mmol, 2-chloro-3-methylquinoline (30 mg, 0.17 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80 ethyl acetate/hexanes eluent ) to give 9 mg (16%) of the title compound as an amorphous foam. mp 185°-193° FDMS: m/e=402.