Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].[CH:14]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=2)=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Agent: [I-]
Product: CCOC(=O)c1ccc(C(=O)C2CCC2)cc1

Procedure:
Intermediate i-4a was prepared from 4-ethoxycarbonylphenyl zinc iodide and cyclobutanecarbonyl chloride following the above procedure as described for intermediate i-1a. 1HNMR (500 MHz, CDCl3): δ 8.13 (d, 2H, J=8.2 Hz), 7.96 (d, 2H, J=8.3 Hz), 4.43 (q, 2H, J=7.1 Hz), 4.04 (dt, 1H, J=6.9, 7.4 Hz), 2.44 (m, 2H), 2.34 (m, 2H), 2.14 (m, 1H), 1.96 (m, 1H), 1.43 (t, 3H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C@@:3]([CH2:7][NH:8]CC1C=CC=CC=1)([OH:6])[CH2:4][OH:5].[H][H]>CO.[Pd]>[NH2:8][CH2:7][C@@:3]([OH:6])([C:2]([F:17])([F:16])[F:1])[CH2:4][OH:5]
Reactant: OC[C@@](O)(CNCc1ccccc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC[C@](O)(CO)C(F)(F)F
Yield: 109.6 %

Procedure:
(S)-3,3,3-Trifluoro-2-{[(phenylmethyl)amino]methyl}-1,2-propanediol (160 mg) was dissolved in methanol (1.5 ml) and hydrogenated using 10% palladium on carbon as the catalyst and the H-cube (Thales) as the hydrogen source. The solvent was carefully evaporated to give a pinkish volatile oil (112 mg) which by 1H NMR still contained 13% starting material. Therefore this was re-dissolved in methanol (2 ml) and re-hydrogenated using the H-cube. The solvent was evaporated to give the title compound as a pink/brown oil (93 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:15]=[CH:14][C:13]([C:24]#[N:25])=[C:12]2[Cl:26])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:26][C:12]1[C:11]2[C:16](=[CH:17][C:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:9]([OH:8])[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:24]#[N:25]
Reactant: COCCOc1cc2ncc(C#N)c(Cl)c2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COCCOc1cc2ncc(C#N)c(Cl)c2cc1O
Yield: 78 %

Procedure:
A mixture of 6-benzyloxy-4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile (512 mg, 1.39 mmol) and 0.9 mL of thioanisole in 7.5 mL of trifluoroacetic acid is heated at reflux for 3 hours then concentrated in vacuo. The residue is treated with ice water and then basified to pH 9-10 by the addition of aqueous ammonium hydroxide. The resultant suspension is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Trituration with diethyl ether provides 302 mg of 4-chloro-6-hydroxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 174-175° C.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[C:18]([CH2:27]N)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>ClCCl>[Cl:16][C:17]1[C:18]([CH2:27][N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][CH:20]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:22]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: ClCCl
Product: FC(F)(F)c1cnc(CN=C(c2ccccc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzophenone imine (1.67 ml) in dry dichloromethane (25 ml) at 10° C. was added (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (2.47 g). The solution was stirred at room temperature for 3 hours and then filtered. The filtrate was evaporated to dryness and purified by silica gel chromatography [light petroleumidiethyl ether (4:1)] to give the title product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]=[CH:12]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[Cl:22]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:22][C:14]1[N:13]=[CH:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=2)[C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)c1ccc(-n2cncc2-c2ccccc2)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-n2cnc(Cl)c2-c2ccccc2)nc1
Temperature: 25 °C
Yield: 30 %

Procedure:
5-(methylsulfonyl)-2-(5-phenyl-1H-imidazol-1-yl)pyridine (50 g), N-chlorosuccinimide (20 g) and azo-bis-isobutyronitrile (500 mg) were dissolved in 3 L tetrachloromethane to allow reflux overnight. The reaction mixture was cooled to room temperature, and the residual solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the target compound (15 g). 1H-NMR (300 MHz, CDCl3): δ 3.12 (3H, s), 6.78 (1H, dd), 7.28 (2H, m), 7.44 (3H, m), 8.06 (1H, dd), 8.25 (1H, s), 9.03 (1H, dd); LC-MS m/z: 335 [M++1], purity (HPLC)>95%.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@@H:3]1[NH2:12].C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>ClCCl.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:12][C@H:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)=[O:26])=[CH:23][CH:22]=1
Reactant: N[C@H]1CCc2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@H]1CCc2ccccc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride (0.9 g) in dichloromethane (15 ml) were added in turn triethylamine (1.71 ml) and 4-fluorobenzoyl chloride (0.58 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give (S)-4-fluoro-N-(1,2,3,4-tetrahydro-naphthalen-2-yl)benzamide (1.26 g).
Reaction SMILES: [CH3:1][C:2]12[CH:17]([CH3:18])[CH:15]3[NH:16][C:12]4=[C:13]([CH2:14]3)[C:8](=[C:9]1[CH2:10][CH2:11]4)[CH:7]=[CH:6][CH2:5][N:4]=[CH:3]2.[CH:19](N(C(C)C)CC)([CH3:21])[CH3:20].C(Br)C=C.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]12[CH:17]([CH3:18])[CH:15]3[N:16]([CH2:21][CH:19]=[CH2:20])[C:12]4=[C:13]([CH2:14]3)[C:8](=[C:9]1[CH2:10][CH2:11]4)[CH:7]=[CH:6][CH2:5][N:4]=[CH:3]2
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2
Reactant: CCN(C(C)C)C(C)C
Solvent: C=CCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1C2=C3CC1C(C)C1(C)C=NCC=CC3=C1CC2
Temperature: 0 °C
Yield: 47 %

Procedure:
To a stirred solution of 1.86 g of 6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 40 ml of dimethylformamide was added 2.85 ml of diisopropylethyl amine. The mixture was cooled to 0° C. and 0.78 ml of allyl bromide in 5.0 ml of dimethylformamide was added, with stirring under nitrogen. The mixture was stirred at 0° for 4.5 hr and then poured into water and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate and ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered and, the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (2% triethylamine/0-10% methanol/ether) and on alumina (ether) to afford 1.02 g (47%) of product. Recrystallization from ether-pentane gave the analytical sample, mp 165°-168° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[N:8]1)=[O:4].[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:21]=[O:22])[CH:28]=3)=[CH:14][CH:13]=2)=[N:8]1)=[O:4]
Reactant: CC(C)(C)C(=O)OCn1cnc(-c2ccc(Br)cc2)n1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cnc(-c2ccc(-c3cccc(C=O)c3)cc2)n1
Temperature: 135 °C

Procedure:
To a solution of [3-(4-bromophenyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethyl-propanoate (0.108 g, 0.32 mmol; IV-30), 3-formylphenyl boronic acid (0.099 g, 0.66 mmol), and PdCl2(dppf).CH2Cl2 (0.024 g, 0.029 mmol) was added 2M Na2CO3 (aq) (0.38 mL, 0.76 mmol). The mixture was subjected to microwave heating (135° C./50 min), cooled, and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (s, 9 H), 6.10 (s, 2 H), 7.63 (t, J=7.69 Hz, 1 H), 7.73 (d, J=8.06 Hz, 2 H), 7.90 (dd, J=14.65, 7.57 Hz, 2 H), 8.15 (m, 1 H), 8.23 (d, J=8.30 Hz, 2 H), 8.39 (s, 1 H), 10.10 (s, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:21][NH:22][CH3:23]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([N:22]([CH3:23])[CH3:21])=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Reactant: CNC
Product: CC(=O)N1CCC(CCC(=O)c2ccc(N(C)C)cc2)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture consisting of 3.2 g of 1-acetyl-4-[2-(4-fluorobenzoyl)ethyl]piperidine and 10 ml of 50% aqueous dimethylamine solution was heated at 100° C. with stirring for 6 hours and then worked up in the same manner as Example 37 to give 1.6 g of colorless crystals melting at 158°-160° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[CH:1]1[CH:2]=[C:3]([CH2:4][C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: Oc1ccccc1
Reactant: C=O
Agent: [W]
Agent: P
Solvent: O
Product: Oc1ccc(Cc2ccccc2O)cc1
Yield: 38.4 %

Procedure:
Several methods are known in the art for the production of dihydroxydiphenylmethanes. Japanese Patent Jpn. Kokai Tokkyo Koho JP 0687775 (CA 121:57131) discloses a method for the condensation of phenol with aqueous formaldehyde using phosphotungstic acid which consists of 10:43:47 ratio of 2,2′-, 2,4′- and 4,4′-dihydroxydiphenylmethane isomers. EP 331, 172: CA 112:7160 discloses a method for reacting phenol with formaldehyde in the presence of an activated clay at 80° C. for 2 hours to give 38.8% of 4,4′-, 15.8% of 2,2′-, and 38.4% of 2,4′-dihydroxydiphenylmethane and 7.0% oligomer JP 63, 238, 632: CA 116: 75045 discloses a method for reacting phenol with formaldehyde in the presence of activated clay catalyst to give 2,2′-, 2,4′-, and 4,4′dihydroxydiphenylmethane in the ratio of 17.1: 41.4:44.5.
Reaction SMILES: Cl.CC(C)CNCC1CCCC1N.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([O:48]CC2C=CC=CC=2)=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH2:44][CH2:43][CH2:42][CH:35]4[CH2:36][N:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:32]3[CH2:31][N:30]2[CH:47]=1)=[O:25]>[Pd]>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([OH:48])=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH2:44][CH2:43][CH2:42][CH:35]4[CH2:36][N:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:32]3[CH2:31][N:30]2[CH:47]=1)=[O:25]
Reactant: CC(C)CN1CC2CCCC2N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12
Agent: [Pd]
Agent: CC(C)CNCC1CCCC1N
Agent: Cl
Product: CC(C)CN1CC2CCCC2N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12

Procedure:
In a manner similar to that described in example Z-35, from racemic-(1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclopentanamine hydrochloride 105 mg, 0.434 mmol) and 16a (56 mg, 0.119 mmol) was prepared racemic-(3aS,5aS,13aS)-N-[(2,4-difluorophenyl)methyl]-5 (2-methylpropyl)-10,12-dioxol-11-[(phenylmethyl)oxy]-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (62 mg, 74%). This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic-(3aS,5aS,13aS)-N-[(2,4-difluorophenyl)methyl]-5-(2-methylpropyl)-10,12-dioxo-11-[(phenylmethyl)oxy]2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (48 mg, 0.081 mmol) and 10% Pd/C (catalytic amount), the title compound was prepared as a white solid after purification by HPLC (80 mg, 75%). 1H NMR (CDCl3) 12.69 (s, 1H), 10.42 (s, 1H), 828 (s, 1H), 7.34 (m, 1H), 6.79 (m, 2H), 4.83 (s, 1H), 4.68-4.58 (m, 3H), 4.29 (m, 1H), 4.14 (m, 1H), 2.01 (m, 1H), 2.46-2.82 (m, 3H), 2.16-2.09 (m, 2H), 1.85-1.61 (m, 5H), 1.39 (m, 1H), 0.88 (m, 6H); ES+MS: 501 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:15][C@H:16]4[NH:27][CH2:26][CH2:25][C@@:22]5([C:23]=3[CH:24]=2)[C@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21]5)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][Cl:39]>CN(C=O)C>[C:1]1([NH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:15][C@H:16]4[N:27]([CH2:36][CH2:37][CH2:38][Cl:39])[CH2:26][CH2:25][C@@:22]5([C:23]=3[CH:24]=2)[C@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21]5)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CCCCl)CC3
Temperature: 50 °C
Yield: 70 %

Procedure:
To a stirred solution of 3-phenylcarbamoyloxymorphinan.HCl 30 (2.8 mg, 0.007 mmol) in dry DMF (0.15 mL) was added potassium carbonate (5.4 mg, 0.021 mmol), 1-bromo-3-chloropropane (1.9 μL, 0.042 mmol) sequentially and the mixture was stirred at 50° C. After starting material disappeared on TLC, solvent was concentrated and column chromatography gave 2.1 mg (70%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.35 (4H, m); 7.10 (2H, m); 6.85 (1H, d); 6.75 (1H, d.d.); 6.28 (1H, s); 4.38 (1H, m); 4.10 (2H, t); 3.80 (2H, t); 3.65 (1H, m); 3.14 (1H, d.d.); 2.83 (2H, m); 2.37 (1H, m); 2.25 (2H, m); 1.00˜1.80 (10H, m).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]3([C:18](=[S:21])[NH:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=[O:17])=[CH:7][N:6]2[CH:22]=1.[BH4-].[Na+].O>CO>[OH:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]1([C:8]1[CH:9]=[CH:10][C:5]2[N:6]([CH:22]=[C:3]([C:2]([F:24])([F:23])[F:1])[N:4]=2)[CH:7]=1)[C:18](=[S:21])[NH:19][CH3:20]
Reactant: CNC(=S)C1(c2ccc3nc(C(F)(F)F)cn3c2)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=S)C1(c2ccc3nc(C(F)(F)F)cn3c2)CCCCC1O
Reaction time: 1 h
Yield: 81.8 %

Procedure:
1.86 g of 1-(2-trifluoromethylimidazo-[1,2-a ]pyridin-6-yl)-N-methyl-2-oxocyclohexanecarbothioamide was suspended in 17 ml of methanol. The obtained suspension was cooled with ice, followed by the addition of 0.08 g of sodium borohydride. The obtained mixture was stirred for one hour, followed by the addition of water. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and freed from the solvent by distillation. The obtained solid was recrystallized from ethyl acetate/n-hexane to give 1.53 g of the title compound as a white solid (yield: 84%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][N:22]3[CH2:23][CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(c1)CCNC2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2csc3ccccc23)cc1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 1,2,3,4-tetrahydroisoquinoline and ethanol essentially as described above in Example 94. Purity by LC/MS=100%, [M+H]+=416.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([C:20](OCC)=[O:21])[C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=[O:21])[C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2cc(C)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Then a solution of the 1-hexyl-3-ethoxycarbonyl-4-hydroxy-6-methyl-2(1H)-quinolinone (12.4 g) in dichloromethane (50 ml ) and methanol (10 ml) was treated with excess diazomethane in ether for 10 mins. This solution was then evaporated. The crude methylation product upon chromatography on silica gel yielded 1-hexyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (11.5 g). The 1-hexyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (7.13 g) in dry toluene (80 ml) was cooled to -78° C. and then a 1M solution of di-isobutyl aluminum hydride (30 ml) was added dropwise in 10 min. After 2.5 hours of stirring at -78° C. the reaction mixture was worked up by stirring with aqueous ammonium chloride/1N hydrochloric acid which was then followed by extraction with methylene chloride. The crude reduction product was chromatographed on silica gel and then crystallized from ethyl acetate/hexane to give 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS(CI): m/e 302 (M+.1); NMR (CDCl3): δ2.42 (s, 3H, Ar--CH3), 4.10 (s, 3H, OCH3), 10.50 (s, 1H, CHO).
Reaction SMILES: O[CH:2]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CS(Cl)(=O)=O.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:34]1([CH:2]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: c1c[nH]cn1
Reactant: CCCCC(O)CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCC(CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC)n1ccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
Diethyl 2-(12-hydroxyhexadecyl)malonate (1.75 g, 4.369 mmol), TEA (0.79 ml, 5.679 mmol) and DMAP (53 mg, 0.437 mmol) were dissolved in dry DCM (20 ml), cooled to 0° C., then methane sulfonyl chloride (0.36 ml, 4.587 mmol) was slowly added. The ice bath was removed, and stirring continued for another 2 h at room temperature. The reaction mixture was diluted with DCM (75 ml), washed with water (50 ml), 0.5 N HCl (10 ml) and brine solution (20 ml), dried on dry MgSO4 and concentrated. The crude compound was mixed with imidazole (595 mg, 8.737 mmol) and stirred at 75° C. for 16 h. The crude compound was purified by silica gel column (2% MeOH in DCM) to give diethyl 2-(12-(1H-imidazol-1-yl)hexadecyl)malonate (640 mg, 32.5%) as a light brown coloured liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12].[N:20]([O-:22])=[O:21].[Na+].[N+]([O-])(O)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:20]([O-:22])=[O:21])[CH:6]=[CH:5][C:4]=1[N:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CN(CC(=O)OC)c1ccccc1OC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COC(=O)CN(CC(=O)OC)c1ccc([N+](=O)[O-])cc1OC
Reaction time: 1 h
Yield: 856.8 %

Procedure:
Dimethyl 2,2′-((2-methoxyphenyl) azanediyl)diacetate (1.98 g, 7.41 mmol) was dissolved in acetic acid (10 mL) at room temperature followed by sodium nitrite (51 mg, 0.74 mmol). The nitric acid (0.49 mL, 8.15 mmol) was added dropwise to reaction mixture. After stirring 1 h, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 ml×3), and dried over MgSO4. The residue was purified by column chromatography using Hex/EtOAc (gradient: 0 to 50% EtOAc) to afford dimethyl 2,2′-((2-methoxy-4-nitrophenyl)azanediyl)diacetate (1.98 g, 86%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.80 (dd, J=8.8, 2.4 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 4.20 (s, 4H), 3.85 (s, 3H), 3.78 (s, 6H); LCMS (ESI) tR: 0.678 min (>99%, ELSD), m/z: 313.2 [M+1]+
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:44][C:45]1[C:46]([C:50]2[N:54]([CH2:55][C:56]([C:58]3[CH:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=3)=[O:57])[C:53]3[CH:65]=[CH:66][CH:67]=[CH:68][C:52]=3[N:51]=2)=[N:47][O:48][N:49]=1>CN(C=O)C.C(OCC)(=O)C.C(OCC)(=O)C.C1CCCCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10](=[O:12])[NH:64][C:61]1[CH:60]=[CH:59][C:58]([C:56](=[O:57])[CH2:55][N:54]2[C:53]3[CH:65]=[CH:66][CH:67]=[CH:68][C:52]=3[N:51]=[C:50]2[C:46]2[C:45]([NH2:44])=[N:49][O:48][N:47]=2)=[CH:63][CH:62]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a stirred solution of 0.06 g of N-BOC-glycine (CAS 4530-20-5) (0.34 mmol; 1.2 eq.) in 1 mL of N,N′-dimethylformamide are added 0.16 g of 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.43 mmol; 1.5 eq.) and 0.1 mL of triethylamine (0.71 mmol; 2.5 eq.) at room temperature. After stirring for 0.5 h at room temperature, a solution of 0.1 g of 2-[2-(4-amino-furazan-3-yl)-benzoimidazol-1-yl]-1-(4-amino-phenyl)-ethanone (CAS 798577-83-0) (0.28 mmol; 1 eq.) in 1 mL of N,N′-dimethylformamide is added. The reaction solution is stirred overnight at room temperature. Then, a solution of 0.03 g of N-BOC-glycine (0.17 mmol; 0.6 eq.) containing 0.08 g of 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.22 mmol; 0.75 eq.) and 0.05 mL of triethylamine (0.35 mmol; 1.25 eq.) in 0.5 mL of N,N′-dimethylformamide is added to the reaction solution at room temperature. The same mixture is added again after additional 24 h and additional 8 h. The reaction mixture is then further stirred for 64 h (total reaction time 120 h). The reaction mixture is diluted with ethyl acetate (10 mL) and then washed with water (10 mL), 10% citric acid aqueous solution (10 mL), brine (2×5 mL), dried over magnesium sulfate, filtered and concentrated to dryness to give crude product. The crude product is subjected to silica gel column chromatography (eluent: ethyl acetate/cyclohexane=1/1 to 4/1). The obtained material is recrystallized from dichloromethane to afford 0.085 g of the desired product as a white powder.