Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([OH:28])=O)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:48][C:49]1[S:50][S:51][C:52](=[S:54])[N:53]=1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([NH:48][C:49]2[S:50][S:51][C:52](=[S:54])[N:53]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(CC(=O)O)cc1OCCCCCCCC
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(CC(=O)Nc2nc(=S)ss2)cc1OCCCCCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
2-[3,4-Bis(octyloxy)phenyl]acetic acid (1.00 g, 2.55 mmol) was dissolved in tetrahydrofuran (8 ml), and 1,1′-carbonyidiimidazole (0.496 g, 3.06 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at room temperature. Sodium hydride (60% oil suspension 0.102 g, 2.55 mmol) was suspended in tetrahydrofuran (8 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.383 g, 2.55 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 16 hours at room temperature. The reaction mixture, with saturated ammonium chloride water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and saturated brine successively, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2-[3,4-bis(octyloxy)phenyl]-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 10) (0.365 g, 33%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][OH:11])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl-].Cl[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1>O>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: CC(C)(C)c1csc(CO)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
A mixture of 4-tert-butyl-2-(hydroxymethyl)thiazole (441 mg, 2.57 mmol), potassium-tert-butoxide (580 mg, 5.17 mmol), tricaprylmethylamminium chloride (100 mg) and methyl 6-chloropyridine-2-carboxylate (660 mg, 3.85 mmol) was stirred at 120° C. for 2 hours. Water was added to the reaction solution and the product formed was extracted with ethyl acetate. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent =hexane:ethyl acetate=20:1 to 10:1) to give methyl 6-(4-tert-butyl-2-thiazolylmethoxy)pyridine-2-carboxylate (198 mg, 0.65 mmol, 25%).
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][N:28]([CH2:12][CH2:13][CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)[CH2:27][CH2:26]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1(c2ccccc2)CCN(CCC2COc3ccccc3O2)CC1

Procedure:
The mixture of 6.68 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 3.54 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is refluxed 48 hours. It is filtered, evaporated and the residue recrystallized from isopropanol, to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan melting at 142°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N+:10]([O-:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:13].[Br:14]Br>CO>[Br:14][CH2:1][C:2]1[CH:11]=[N+:10]([O-:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:13]
Reactant: BrBr
Reactant: Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CO
Product: [O-][n+]1cc(CBr)[n+]([O-])c2ccccc21
Reaction time: 1 h
Yield: 32 %

Procedure:
To a thick slurry of 106 g. (0.6 mole) of 2-methyl quinoxaline 1,4-dioxide in 400 ml of methanol was added with stirring over a period of 1 hour, 96 g. (0.6 mole) of bromine. The reaction was then stirred for 5 days at room temperature. The reaction mixture was filtered and the collected yellow solid was washed with 200 ml. of ether. This solid was air dried to obtain 50 g. (32percent yield of the title compound, mp-158°-159°.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[O:10])[CH2:6]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[N:26](OCCCC)=[O:27]>O1CCCC1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4](=[N:26][OH:27])[C:5](=[O:10])[CH2:6]2
Reactant: CCCCON=O
Reactant: CN1C2CCC1CC(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C2CCC1C(=NO)C(=O)C2
Temperature: 0 °C
Yield: 26 %

Procedure:
A solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (2.79 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) under nitrogen was cooled (-68° C.) and treated (via syringe) with 1.0N lithium bis(trimethylsilyl)amide/tetrahydrofuran (36 mL, 36 mmol) at a rate to keep the pot temperature below -55° C. The mixture was warmed to 0° C., then recooled (-68° C.), and treated dropwise with a solution of n-butyl nitrite (2.6 mL, 22 mmol) in anhydrous tetrahydrofuran (15 mL) at a rate to keep the pot temperature below -60° C. The mixture was warmed to room temperature over one h, stirred for one h, and quenched with saturated ammonium chloride (15 mL). The organic layer was separated and the aqueous solution was extracted with toluene (50 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel (eluted with 9:1 ethyl acetate/methanol, then with 3:2 ethyl acetate/methanol) to afford, first, 8-methyl-8-azabicyclo[3.2.1]octane-2,3-dione-2-oxime (0.43 g, 13%, beige solid), then recovered starting material (1.40 g). Product yield was 26% based on recovered starting material.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH2:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1coc(-c2ccccc2)n1
Product: O=C(NCCc1coc(-c2ccccc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 25 %

Procedure:
This compound was synthesized from 2-(2-phenyloxazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mgs, yield 25%). 1H NMR (CDCl3) δ 8.59 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.05 (m, 2H), 7.62-7.56 (m, 3H), 7.43 (m, 2H), 3.84 (m, 2H), 2.93 (m, 2H). MS (ESI) m/z: Calculated for C21H15F3N4O3: 428.11. found: 429.1 (M+H)+.
Reaction SMILES: CN(C)C=O.FC(F)(F)S(O[C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][C:15]([C:25]([O:27][CH3:28])=[O:26])=[CH:14][N:13]=1)(=O)=O.[C:31]([C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1)#[CH:32].N>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.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:18]([C:17]1[C:12]([C:32]#[C:31][C:33]2([OH:41])[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[N:13][CH:14]=[C:15]([C:25]([O:27][CH3:28])=[O:26])[CH:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COC(=O)c1cnc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
50 ml of N,N-dimethylformamide was added to a mixture of 2.0 g of 3-benzyl-5-methoxycarbonyl-2-pyridyl trifluoromethanesulfonate, 742 mg of 3-ethynyl-3-quinuclidinol, 1.5 g of tetrakis(triphenylphosphine)palladium(0), 374 mg of cuprous iodide and 2.7 ml of triethylamine, followed by heating under stirring for one hour in an oil bath kept at 60° C. in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using chloroform/methanol/aqueous 36% ammonia (46:3:0.3) as an eluent for separation and purification, to give 1.1 g of the target compound.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]([C:13]([C:15]2[CH:16]=[C:17]([N:23](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:18]([O:21][CH3:22])=[N:19][CH:20]=2)=[O:14])=[CH:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:23][C:17]1[CH:16]=[C:15]([C:13]([C:6]2[C:7]3[CH:8]=[N:9][CH:10]=[CH:11][C:12]=3[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[O:14])[CH:20]=[N:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ncc(C(=O)c2cn(C(C)C)c3ccncc23)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(C(=O)c2cn(C(C)C)c3ccncc23)cc1N
Temperature: 25 °C

Procedure:
To a solution of di-tert-butyl {5-[(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)carbonyl]-2-methoxypyridin-3-yl}imidodicarbonate (Preparation 32, 250 mg, 0.5 mmol) in DCM (2.5 mL) at 0° C. was added TFA (0.75 mL) dropwise and the reaction stirred warming to room temperature for 5 hours. The reaction was basified by the addition of saturated aqueous NaHCO3 solution and extracted into DCM (3×30 mL). The organic layers were combined, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: C1C2C=C3C(=O)C(C=2C=CC=1)C=CC=C3.Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1([CH3:34])[C:30]2[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:33]>>[CH3:32][O:31][C:27]1[CH:28]=[CH:29][C:30]2[C:21]3([CH3:34])[C:22](=[O:33])[CH:23]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:24][C:25]=2[CH:26]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2(C)CCCCCl
Agent: O=C1C2=Cc3ccccc3C1C=CC=C2
Product: COc1ccc2c(c1)CC1CCCCC2(C)C1=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl)- 5,10-methano-5H-benzocyclononen-12-one, there is obtained from 30.5 g. of 1-(4-chlorobutyl)-1-methyl-6-methoxy-2-tetralone 15 g. of the title product, b.p. 140° to 145° C. (0.5 mm.).
Reaction SMILES: [CH2:1]([C@@H:7]1[C@@H:12]([OH:13])[C:11]([CH3:16])([CH2:14][OH:15])[O:10][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C@@H:7]1[C@@H:12]([OH:13])[C:11]([CH3:16])([CH2:14][O:15][S:18]([CH3:17])(=[O:20])=[O:19])[O:10][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC[C@H]1C(=O)OC(C)(CO)[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@H]1C(=O)OC(C)(COS(C)(=O)=O)[C@@H]1O

Procedure:
2-(R)-Hexyl-3-(R)-hydroxy-4-methyl-4-hydroxymethylbutyrolactone (prepared as described in example 7) is reacted with 1 eq. of methanesulfonylchloride and 3 eq. of triethylamine in dry methylene chloride at 0° C. to afford 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-methanesulfonyloxymethylbutyrolactone
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f2) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][C:13]([C:20]([OH:22])=O)=[C:12]2[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@@H:28]([CH3:30])[NH2:29]>>[CH3:25][O:26][C:27](=[O:31])[CH:28]([NH:29][C:20]([C:13]1[N:14]=[C:15]([Cl:19])[C:16]2[C:11]([C:12]=1[OH:23])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:18][CH:17]=2)=[O:22])[CH3:30]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C(O)c1nc(Cl)c2ccc(OCc3ccccc3)cc2c1O
Agent: Cl
Product: COC(=O)C(C)NC(=O)c1nc(Cl)c2ccc(OCc3ccccc3)cc2c1O

Procedure:
6-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with D-Alanine methyl ester hydrochloride, 0.150 g, analogously to Example A-1a). 0.205 g of off-white, solid product were obtained, MS-(+)-ion, M+1=415.0 amu.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].C(O[C:12]1(O[Si](C)(C)C)[CH2:14][CH2:13]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH:12]1([N:6]2[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:14][CH2:13]1
Reactant: N#CC1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: N#CC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyanopiperidine (2.5 g, 23 mmol, J. Org. Chem. 21, 984-986, 1957) in methanol (16 mL) and THF (65 mL) was added with stirring (1-ethoxycyclopropoxy)-trimethylsilane (7.0 g, 40 mmol), glacial acetic acid (2.3 mL) and sodium cyanoborohydride (3.3 g, 53 mmol). When addition was complete the mixture was stirred 1 h at ambient temperature and then heated overnight at 65° C. under an atmosphere of nitrogen. The solvent was evaporated and to the residue was added water (30 mL) and 1N HCl until pH 1. The mixture was washed with diethyl ether (50 mL) and the acidic aqueous phase was saturated with potassium carbonate. The alkaline mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (MgSO4) and the solvent was evaporated. This afforded 3.2 g of 1-cyclopropyl-4-cyanopiperidine. 1H NMR (400 MHz, CDCl3) δ 0.37-0.50 (m, 4H), 1.59-1.66 (m, 1H), 1.77-1.94 (m, 4H), 2.4-2.9 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4](=[O:18])[C:5]([C:13]([O:15]CC)=[O:14])=[CH:6][NH:7]2.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>CN(C=O)C.O.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4](=[O:18])[C:5]([C:13]([OH:15])=[O:14])=[CH:6][N:7]2[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]c2c(F)ccc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(F)ccc(F)c32)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (5.0 g), potassium iodide (3.3 g) and potassium carbonate (4.1 g) in DMF (100 mL) was added 1-(chloromethyl)-4-methoxybenzene (4.6 g), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in ethanol-THF (1:1, 40 mL), 1 N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with water, neutralized with 1 N hydrochloric acid (20 mL), and the precipitate was collected by filtration, washed with water, and dried to give the title compound (4.4 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][C:18](=O)[NH:17][CH:16]([CH2:21][CH3:22])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:7]([N:14]1[CH2:19][CH2:18][NH:17][CH:16]([CH2:21][CH3:22])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCC1NC(=O)CN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminium hydride (0.87 g; 22.9 mmol) in anhydrous THF (20 ml) was added dropwise a solution of 1-benzyl-3-ethylpiperazine-2,5-dion (1.50 g; 6.46 mmol) in anhydrous THF (10 ml) under ice-cooling. After stirring at room temperature for 18 hours, a mixture of water (0.25 ml) and THF (5 ml) and 2N-aqueous sodium hydroxide solution (0.5 ml) were added dropwise sequentially under ice-cooling. The mixture was stirred at room temperature for 1 hour. After filtration of aluminium hydroxide, the filtrate was condensed under reduced pressure. To the residue were added ethyl acetate and brine to separate. The organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to give 1-benzyl-3-ethylpiperazine as pale yellow oil (1.29 g; 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[CH3:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[CH3:13])=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)cc1C
Product: COC(=O)c1nc(C)sc1-c1ccc(C)cc1C

Procedure:
prepared by reaction of 3-Chloro-3-(2,4-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.96 min; [M+H]+=262.3.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CN(C=O)C.C(O)(=O)C>[CH:24]1([N:2]2[CH2:3][CH2:4][CH:5]([O:8][C:9]3[N:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=4)=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCCC1
Reactant: O=c1ccc(-c2ccc(OC3CCNCC3)nc2)n[nH]1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccc(OC3CCN(C4CCCC4)CC3)nc2)n[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6-[6-(piperidin-4-yloxy)-pyridin-3-yl]-2H-pyridazin-3-one hydrochloride (407 mg, 1.18 mmol) in a mixture of DMF (5 mL), methanol (15 mL), and acetic acid (250 μL) was added cyclopentanone (314 μL, 3.54 mmol), followed by sodium cyanoborohydride (371 mg, 5.9 mmol). After stirring at 60° C. for 2 h, the reaction was concentrated, partitioned between dichloromethane/1N sodium carbonate, washed with water/brine, dried over sodium sulfate, and concentrated. The product was purified using prep TLC plates (9:1 dichloromethane:methanol) (25%); Mp 233-237° C.; MS m/z 341 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][O:20][C:21](=[O:28])[CH:22](Br)[CH2:23][CH2:24][CH2:25][Br:26]>>[CH3:19][O:20][C:21](=[O:28])[CH:22]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10][CH2:11]1)[CH2:23][CH2:24][CH2:25][Br:26]
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1
Reactant: COC(=O)C(Br)CCCBr
Product: COC(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 97 %

Procedure:
In analogy to the procedure described in example 15B, 1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one (example 15 A) and (rac)-2,5-dibromo-pentanoic acid methyl ester gave the title compound in 97% yield as yellow oil. MS: 453.1 (1Br, MH+).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:4]
Reactant: CCCCCCCCCCO
Reactant: CSCCC(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 4 neck 1 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (125 g, 832.2 mmol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-decanol (238 mL, 1248 mmol), sodium hydrogen sulfate (1.998 g, 16.64 mmol), and toluene (625 mL). The reaction was heated to reflux with removal of water (16 mL) during the course of about 6 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and the organic layer was washed with saturated NaHCO3 (1×300 mL), DI water (1×300 mL) and brine (2×300 mL), dried over sodium sulfate, filtered and evaporated to give an amber oil (395.5 g). The oil was purified by kugelrohr distillation at 110° C. and 0.1 Torr vacuum to give an oil (105.23 g, 43.5%). m/z 313 (MNa+);
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]([NH2:30])[CH3:29])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]([F:25])([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1ccc(OC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (513 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (666 mg, 2.39 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (600 mg, 2.17 mmol, Amine-83, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][N:10]=1)C1C=CC=CC=1.I[Si](C)(C)C.CO>ClCCl>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:12]1[C:13](=[O:15])[NH:14][C:9](=[O:8])[NH:10][CH:11]=1
Reactant: c1ccc(COc2ncc(-c3cccs3)c(OCc3ccccc3)n2)cc1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]cc(-c2cccs2)c(=O)[nH]1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of 2,4-bis(benzyloxy)-5-(thiophen-2-yl)pyrimidine (Prep21, 20 g, 53.5 mol) in dry dichloromethane (400 ml), iodotrimethylsilane (28.8 g, 0.14 mol) was added at room temperature. The resulting solution was stirred for 3 hours. Then methanol was added, the precipitate was filtered and the solid was recrystallized with methanol twice, to afford 7 g of the title compound (y=67.3%)