Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3B3OC(C)(C)C(C)(C)O3)[S:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:33]3[O:34][C:35]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[CH:36][C:37](=[O:39])[CH:38]=3)[S:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Sc1cccc(B3OC(C)(C)C(C)(C)O3)c1S2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 100 °C
Yield: 127.4 %

Procedure:
[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thianthren-2-yl]-carbamic acid tert-butyl ester (8.34 g, 18.24 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (3)(4.72 g, 21.89 mmol) and grinded K2CO3 (5.04 g, 36.48 mmol) were dissolved in dry 1,4-dioxane (100 ml). The mixture was degassed for 15 minutess and Pd(PPh3)4 (1.02 g, 0.91 mmol) was then added The dark brown mixture was heated to 100° C. under an atmosphere of N2 for 24 hour. The reaction mixture was concentrated in vacuo and water (100 ml) was added. The brown solid was filtered, washed with water, dried overnight in a vacuum desiccator and was used without any further purification to give the title compound (11.87 g). m/z (LC-MS, ESP), RT=4.61 min, (M++1)=511.2
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](O)([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:29])(=[O:6])=[O:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][C:24]([O:26][CH3:27])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:29])(=[O:5])=[O:6])([CH3:2])[CH3:3]
Reactant: COC(=O)CC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 6.0 g. of 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-methoxycarbonylmethylbenzyl)benzimidazole (from Example 4) and 6.0 g. of p-toluenesulfonic acid in 150 ml. of chloroform was heated at reflux for three hours. The solution was cooled to room temperature and washed two times with saturated aqueous sodium bicarbonate solution, and two times with water. After drying the solution over sodium sulfate, the solvent was removed by evaporation under reduced pressure to provide 5.5 g. (96% yield) of 1-isopropylsulfonyl-2-amino-6-(α-methoxycarbonylmethylenebenzyl)benzimidazole. M.P. 160°-165° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=2[F:11])[CH2:3][CH2:2]1.[C:12]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[CH2:25][CH2:24]OS2(=O)=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][CH2:25][CH2:24][C:8]2[CH:7]=[CH:6][C:5]([F:11])=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:9]=2)=[CH:28][CH:29]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: Fc1ccc(I)cc1C1CC1
Reactant: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C3CC3)c2)cc1
Yield: 28.3 %

Procedure:
The title compound was synthesized in analogy to example S6-C using 2-cyclopropyl-1-fluoro-4-iodobenzene (100 mg, 0.38 mmol) and 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (103 mg, 0.38 mmol). The residue was purified by flash column chromatography to give the desired product (35 mg, 28%) as a colorless oil. MS (ISP) 326.3 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:18][CH:19]1CCOC(=O)CCCCCCOCC1>>[CH3:1][CH:2]1[CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:19][CH2:18][O:5][CH2:4][CH2:3]1
Reactant: CC1CCOCCCCCCC(=O)OCC1
Reactant: CC1CCOCCCCCCCC(=O)OCC1
Product: CC1CCOCCCCCCCCCC(=O)OCC1

Procedure:
Odor: Animalic, musk, sweet, erogenous, warm-powdery.--IR (film): ν=1735 cm-1 (νC=O), 1117/1151 cm-1 (νasO--C--C), 1254 cm-1 (νasC--C(=O)--O), 1361 cm-1 (δCH3), 1060 cm-1 (νasC--O--C).--1H-NMR (CDCl3): δ=0.92 (d, J=6.8 Hz, 3H, 14-Me), 1.29-1.56 (m, 14H, 4-H2 -9-H2, 13-H2), 1.61-1.67 (m, 3-H2, 15-Hb), 1.79 (ddt, 14.0, 8.4 and 5.2 Hz, 1H, 15-Ha), 1.87 (mc, 1H, 14-H), 2.33 (dd, J=6.8 and 6.0 Hz, 2H, 2-H), 3.34-3.50 (m, 4H, 10-,12-H2), 4.15 (ddd J=11.2, 6.0 and 5.2 Hz, 1H, 16-Hb), 4.18 (ddd, J=11.2, 8.4 and 4.4 Hz, 1H, 16Ha). --13C-NMR (CDCl3): δ=18.54 (q, 14-Me), 24.80/26.15 (t, C-3,-8), 26.17 (d, C-14), 27.31/27.66/27.791/28.22 (t, C-4-C-7), 29.15 (t, C-9), 34.02 (t, C-2), 35.57 (t, C-15), 37.00 (t, C-13), 62.14 (t, C-16), 68.05/70.77 (t, C-10,-12), 174.14 (s, C-1). --MS (EI): m/z (%)=55 (100) [C4H7⊕ ], 83 (71) [C6H11⊕ ], 99 (33) [C6H11O⊕ ]113 (13) [M⊕ --C10H21O]153 (15) [M⊕ --C6H13O2 ], 169 (16) [M⊕ --C6H13O]171 (9) [C10H19O2⊕ ], 227 (1) [M⊕ --C2H3O], 241 (2) [M⊕ --CHO], 270 (1) [M⊕].--C16H30O3 (270.41): calculated C 71.07, H 11.18; found C 71.37, H 11.13.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[C:14]1([CH:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1C(c1ccccc1)c1ccccc1
Reaction time: 0.3 h
Yield: 43 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 50.8 g (0.25 mole) of benzhydryl chloride. The reaction mixture was heated with rapid stirring to 100° over 0.3 hr, held at 100° for 1.5 hours and poured into 1.5 l of H2O. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness under reduced pressure leaving 27 g (43%) of a semi-solid. The crude product was washed with 100 ml of ether, air dried and dried at 60° for 2 hours to give 19 g (30%) of a white solid, m.p. 200°-202°. Recrystallization from acetonitrile provided an analytical sample, m.p. 201°-203°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: Cc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(n1)NCCC2
Reaction time: 24 h
Yield: 82.5 %

Procedure:
The compound was prepared according to the procedure as described in WO 0033838. To a solution of 2-methyl-1,8-naphthyridine (2 g, 13.9 mmol) in ethanol (35 ml) was added 10% Pd/C, and the reaction mixture was stirred under H2 (10 psi) for 24 hours. Palladium was filtered out through celite and washed with excess ethanol. The filtrate was concentrated under vacuum to give 1.7 g (83%) pink solid. NMR (CD3OD) δ 1.82-1.87 (m, 2H), 2.22 (s, 3H), 2.65-2.76 (m, 2H), 3.33-3.36 (m, 2H), 6.32 (d, 1H, J=7.25 Hz), 7.07 (d, 1H, J=7.38 Hz). Mass spectrometry: 149.15 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:32])[CH2:19][C:18](=[O:20])[CH:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:15]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:18](=[O:20])[CH2:19][C:14]([CH3:32])([CH3:13])[CH2:15][C:16]=3[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: CC1(C)CC(=O)C=C(Nc2cccc(C(F)(F)F)c2)C1
Solvent: ClCCl
Product: CC1(C)CC(=O)C2=C(C1)N(c1cccc(C(F)(F)F)c1)C(=O)NC2c1ccc(Br)cc1

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (435 mg, 1.77 mmol) in dichloromethane (5 mL) is added to a solution of 5,5-dimethyl-3-(3-(trifluoromethyl)-phenylamino)cyclohex-2-enone (intermediate 8, 500 mg, 1.77 mmol) in dichloromethane (15 mL) and the mixture is heated at reflux over night. All volatiles are evaporated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 389 mg; ESI mass spectrum: [(79Br)-M+H]+=493, [(81Br)-M+H]+=495; Retention time HPLC: 1.38 min (Z002—002).
Reaction SMILES: [CH:1](/[C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc2ccccc2c2cc(/C=C/c3ccccc3)cnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc2ccccc2c2cc(CCc3ccccc3)cnc12
Reaction time: 3 h

Procedure:
To a solution of (E)-2-styrylbenzo[f][1,7]naphthyridin-5-amine (Example 32) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-phenethylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 1H), 8.32 (d, 1H), 8.10 (dd, 1H), 7.63 (dd, 1H), 7.51 (m, 1H), 7.03-7.32 (m, 6H), 6.16 (bs, 2H), 3.11 (t, 2H), 2.97 (t, 2H). LRMS [M+H]=300.1.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH:16]=O)[CH2:4][CH3:5].[BH4-].[Na+]>CO>[CH3:1][NH:2][CH2:16][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[CH2:3][CH2:4][CH3:5]
Reactant: CCCc1c(C=O)ccc2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(CNC)ccc2ccccc12
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 2.0 M methylamine in methanol (20 mL) was added to 1-propyl-naphthalene-2-carbaldehyde (0.983 g, 4.95 mmol) under N2 and allowed to stir for 18 h. The solution was concentrated under reduced pressure. Then the resulting dark yellow oil was solvated in EtOH (20 mL) under N2. To the solution was added NaBH4 (0.187 g, 4.95 mmol) and the mixture allowed to stir for 6.5 h. The reaction was concentrated under reduced pressure, then solvated in 1 N NaOH (20 mL) and extracted with Et2O (3×50 mL). The organics were combined, washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (0.94 g, 89%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.87-7.73 (m, 4H), 7.51-7.43 (m, 3H), 3.53 (m, 1H), 2.09 (s, 3H), 1.70-1.52 (m, 2H), 1.26-1.12 (m, 2H), 0.87-0.79 (m, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:1][CH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2noc(C3CC(O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2noc(C3CC(OS(C)(=O)=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.5 h

Procedure:
To a stirring suspension of N-(5-(5-(3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (220 mg, 0.565 mmol) (19) in anhydrous DCM (10 mL) at 0° C. was added DIEA (197 uL, 1.13 mmol) and methanesulfonyl chloride (542 uL, 0.678 mmol). The reaction was stirred to room for 30 minutes. The crude product was purified by silica chromatography to give 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl methanesulfonate (81). MS m/z 468.13 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30](O)=[O:31])=[CH:24]2>>[CH2:13]([C@H:3]([NH:2][C:30]([C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([Cl:20])=[CH:29][CH:28]=2)=[O:31])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one hydrochloride (0.8 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.9 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hour reaction time) and the product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes followed by trituration from 1:1 ether-hexanes. Yield 266 mg, 76%; HPLC (60/40) 4.09 minutes (99%); PBMS 426/428 (MH+, 100%);
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.Cl>C1COCC1>[CH3:9][C:7]1[CH:8]=[C:3]([B:11]([OH:16])[OH:12])[CH:4]=[C:5]([CH3:10])[CH:6]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Magnesium turnings (1.44 g, 59.43 mmol) were covered with dry THF (18.8 mL) in a dried, nitrogen filled flask fitted with an addition funnel and reflux condenser. To this was added 5-bromo-m-xylene (10 g, 54.03 mmol) in THF (15 mnL) after initiation of the Grignard reaction. The addition was carried out over several minutes and the reacton mixture was heated at reflux for 1-2 hours until most of the magnesium had reacted. The reaction mixture was then cooled and transferred to an addition funnel fitted to an nitrogen filled flask containing triisopropyl borate (24.9 mL) at −70° C. The dropwise addition was carried out over several minutes and the mixture warmed to room temperature and stirred overnight. The grey solution was poured onto 2 M HCl and immediately turned yellow. The solution was extracted with Et2O and the Et2O fractions were combined, dried over MgSO4 and the solvent was removed in vacuo to provide the desired product (2.41 g): m.p.249-251° C.; 1H NMR (CDCl3) d 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD3OD) d 21.36, 133.28, 134.39, 137.48.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]1([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#N)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O:26]CC)C.S(=O)(=O)(O)O>C(Cl)Cl>[C:10]1([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[O:26])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: N#Cc1ccccc1C1=CCCCC1
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=Cc1ccccc1C1=CCCCC1

Procedure:
360 ml. (0.36 mol) 1M DIBAH solution in methylene chloride was added dropwise in the course of 1.5 hours, while cooling to -15° to -10° C., into a solution of 60.5 g. (0.33 mol) o-(1-cyclohexenyl)-benzonitrile in 500 ml. anhydrous diethyl ether, stirred for a further hour at 0° C., subsequently for 3 hours at ambient temperature and decomposed with 5N sulphuric acid. The precipitate obtained was filtered off with suction and the organic phase was washed with an aqueous solution of sodium chloride, dried and evaporated. The aldehyde obtained was used for the following stage without further purification (crude yield 95% of theory). NMR,(60 MHz, CDCl3, ppm): 10.25 (1H, s, --CHO); 6.90-8.10 (4H, m. aromat. protons); 5.70 (1H, m, olef. proton); 1.05-2.50 (8H, m, cyclohexenyl radical).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C@@H:4]([CH3:12])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:37][C:16]([F:15])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23](/[CH:26]=[C:10]2/[C:6]([NH:5][C@@H:4]([C:3]([N:2]([CH3:1])[CH3:14])=[O:13])[CH3:12])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:22][CH2:21]1
Reactant: C[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-D-alaninamide (1.02 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.93 g) in 2-propanol (10 mL) was added piperidinium acetate (826 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.30 g)
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH2:26][Cl:27])=[O:23]>>[Cl:27][CH2:26][CH2:25][O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23]
Reactant: O=C(Cl)OCCCl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)OCCCl)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-chloroethyl chloroformate, there is obtained ethyl N-(2-chloroethoxycarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil, mass spectrum m/e: M+ 372 (4), 343 (12), 293 (10), 263 (72), 194 (100), 178 (86), 165 (79);
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30])[CH3:25]>>[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:30])[CH3:25]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCOc1ccccc1C(=O)Nc1ccc(C(=O)OC)c(N)c1
Product: CCOc1ccccc1C(=O)Nc1ccc(C(=O)OC)c(NC(=O)c2ccccc2OCC)c1

Procedure:
By the procedure similar to that described in Example 21, methyl 2-amino-4-(2'-ethoxybenzamido)-benzoate and 2-ethoxybenzoylchloride were reacted and treated to obtain crystals. Recrystallization from acetone gave methyl 2,4-bis(2'-ethoxybenzamido)-benzoate having a melting point between 199° - 200°C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1Cl>>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:13]=[CH:14][C:15]=1[O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Product: Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1

Procedure:
reacting the salt of m-cresol with 3,4-dichlorobenzotrifluoride to form a 3-(2-chloro-4-trifluoromethylphenoxy)toluene;
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1>CC(O)=O.C(O)C.[Ni]>[NH2:8][CH2:7][C:6]1[C:9]([CH3:11])=[CH:10][C:3]([CH2:2][OH:1])=[N:4][C:5]=1[O:12][CH3:13]
Reactant: COc1nc(CO)cc(C)c1C#N
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1nc(CO)cc(C)c1CN
Yield: 58.6 %

Procedure:
A clear solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (0.50 g, 2.81 mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete (crude contained 57% product and 43% dimeric side product). The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 12% (5% NH4OH in MeOH) in CH2Cl2) (step gradient to 8% to elute off the dimeric side product then to 12% to elute off the product). The pure fractions were combined and evaporated to dryness under vacuum to give the product (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol (0.30 g, 1.646 mmol, 58.7% yield) as a white solid. MS(ES)+m/e 183.1 [M+H]+,166.1 [M+H]+—NH3.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)Cl.Cl>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:18](=[O:20])[CH3:19]
Reactant: NCc1ccccc1Br
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 1-(2-bromophenyl)methanamine hydrochloride salt (1 eq.) in CH2Cl2 (0.3M) at room temperature was added triethylamine (2.1 eq) then acetic anhydride (1.1 eq.). The mixture was stirred at room temperature for 6 h, poured in aqueous HCl (0.5N) and extracted with CH2Cl2. The organic extract was dried over MgSO4 filtered and concentrated to afford the desired compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=1[NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=1[N:24]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:8]
Reactant: CCc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)OC)c(N(CCCC(=O)OC)C(=O)OC(C)C)cc1C(F)(F)F
Temperature: 90 °C
Yield: 78.3 %

Procedure:
Add 4-bromo-butyric acid methyl ester (74.30 g, 410.46 mmol) to a mixture of 5-ethyl-2-isopropoxycarbonylamino-4-trifluoromethyl-benzoic acid methyl ester (39.05 g, 117.16 mmol) and cesium carbonate (114.65 g, 351.88 mmol) in N,N-dimethylformamide (800 mL). Heat the mixture at 90° C. for 4 h and the allow it to cool to room temperature. Filter the mixture through Celite then dilute the mixture with water (2 L) and ethyl acetate (2 L). Wash the organic layer with water (500 mL) and brine (500 mL). Dry the organic layer over anhydrous sodium sulfate and filter. Remove the solvents under reduced pressure and purify the resulting residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a white solid (39.75 g, 78%): TLC Rf 0.42 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.0-1.10 (m, 3H), 1.22-1.32 (m, 6H), 1.78-1.89 (m, 2H), 2.37-2.40 (m, 2H), 2.82-2.89 (m, 2H), 3.41-3.80 (m, 5H), 3.89 (s, 3H), 4.78-5.02 (m, 1H), 7.43 (s, 1H), 7.91 (s, 1H).