Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C1CCN2C(=NCCC2)CC1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C>[CH2:13]([O:12][C:10]([N:1]1[CH2:9][CH:7]([O:8][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:6][CH:2]1[C:3]([OH:5])=[O:4])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC(C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 140.6 %

Procedure:
A solution of Z-Hyp-OH (1, 300 g, 1.13 mol), TEA (395 mL, 2.83 mol), and DBU (17.2 g, 1.13 mol) in DMF (1.25 L) was stirred in a cold water bath while a suspension of TBS-Cl (188 g, 1.24 mol) in DMF (270 mL) was added slowly at 21-26° C. [Note: moderately exothermic]. The resulting thin suspension was stirred for 22 h at ambient temperature. The reaction mixture was cooled to 2° C. and quenched with water (1.54 L) at 26° C. [Note: the pH of the aqueous layer was 8.5-9.0]. MTBE (3 L) was added and the mixture was acidified to pH 3-4 with conc. HCl (168 g) at 17-19° C. The organic layer was separated and washed with water (2×1.5 L). The organic layer was concentrated in vacuo and dried by additional MTBE distillation. Toluene (2×500 mL) was added and distilled to remove moisture to provide 603 g of 2 as a light yellow-colored oil [Note: the water content by KF analysis was 508 ppm]. Based on drying a small sample of 2 to a solid, the contained weight of 2 was 412 g (96% yield, not corrected for purity). 1H NMR (300 MHz, CDCl3): δ7.34 (m, 3H), 7.29 (m, 2H), 5.24-5.11 (m, 2H), 4.52 (m, 1H), 4.43 (m, 1H), 3.64-3.42 (m, 2H), 2.27-2.09 (m, 2H), 0.85 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (75 MHz, d6-DMSO), mixture of rotomers: δ178.7, 178.4, 159.3, 158.9, 141.9, 141.8, 133.4, 133.3, 132.8, 132.6, 132.3, 131.9, 75.3, 74.6, 71.0, 71.0, 62.8, 62.3, 60.1, 59.7, 44.4, 43.4, 30.6, 30.6, 22.6, 22.6, 0.1, 0.0 ppm. Mass spectrum (ESI), m/z 379.5 [(M)+; calcd for C19H29NO5Si: 379.5].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: FC(F)(F)CI
Reactant: N#Cc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(OCC(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
To a solution of 2-fluoro-5-hydroxy-benzonitrile (Alfa Aesar, 137 mg, 1.0 mmol) was added 2-iodo-1,1,1,-trifluoroethane (117 L, 1.2 mmol) and potassium carbonate (165 mg, 1.2 mmol) in DMF (20 mL) and stirred at RT for 24 hours. The reaction was dissolved into EtOAc and washed with water three times and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using hexanes:ethyl acetate 5:1 to give the tile compound as white solid (105 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]([O:15][N:16]=[C:17]([NH2:20])[CH2:18][CH3:19])=O)[O:4]1>COCCOCCOC>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[O:15][N:16]=[C:17]([CH2:18][CH3:19])[N:20]=2)[O:4]1
Reactant: CCC(N)=NOC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: COCCOCCOC
Product: CCc1noc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)n1
Temperature: 25 °C

Procedure:
A solution of N′-({[(3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]carbonyl}oxy)propanimidamide (Preparation 12) (5.85 g, 20 mmol) in 2-methoxyethyl ether (20 ml) was heated at 120° C. for four hours. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The final traces of 2-methoxyethyl ether were removed by co-evaporation with first xylene and then toluene. The title compound was obtained as a dark orange oil (5.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:22]([O-])=O)[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:22])[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Suspended 236 mg of 6-chloro-7-(4-methyl-piperazin-1-yl)-8-nitro-9H-β-carboline in 100 ml of methanol and added 10% Pd/C(48 mg) under argon. The flask was flushed with hydrogen (3×) and the reaction mixture was stirred under a hydrogen atmosphere at RT overnight. The reaction mixture was filtered and Pd/C was removed using a pad of celite. The reaction mixture was evaporated to remove solvent and purified by flash chromatography to give 119 mg (55% yield) of the desired 6-chloro-7-(4-methyl-piperazin-1-yl)-8-amino-9H-β-carboline.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[CH3:30][NH:31][CH3:32].Cl.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2
Reactant: CNC
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of bromide (204) prepared as described in example 173 (0.12 g, 0.27 mmol) in dimethylacetamide (4 mL) was added the amine, dimethylamine (25 mol eq., 0.85 mL in this case as an 40% aqueous solution). The reaction vessel was sealed and heated at 80° C. with stirring for 18 h, before being diluted with water. The resulting solution was then acidified by the dropwise addition of concentrated hydrochloric acid and the pH was then adjusted to approximately pH=9 by the addition of solid potassium carbonate. The precipitated product was either collected by filtration and washed with water and diisopropyl ether before being dried or extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with methanol/dichloromethane (1:9 to 1:4), followed by trituration in ethyl acetate/hexane gave amine (208) (52 mg, 47%) as a yellow powder, mp 185–189° C. 1H NMR δ [(CD3)2SO] 11.05 (s, 1H), 9.34 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.64 (m, 2H), 7.56 (d, J=8.9 Hz, 1H), 7.47 (m, 3H), 7.14 (dd, J=8.9, 2.4 Hz, 1H), 4.48 (t, J=6.6 Hz, 2H), 2.16 (t, J=6.5 Hz, 2H), 2.08 (s, 6H), 1.90 (m, 2H). Found: C, 71.98; H, 5.67; N, 10.14. C25H23N3O3.1/4H2O requires: C, 71.84; H, 5.67; N, 10.05.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>CC(O)C>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2c(Cl)nccc2c1I
Solvent: CC(C)O
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1I
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
To a solution of 1-chloro-5-iodo-6-methylisoquinoline (0.400 g, 1.32 mmol) in IPA (5.00 ml), charged to a 5 mL mircowave reaction vessel, 3-(trifluoromethyl)aniline (0.329 ml, 2.64 mmol) was added. The reaction mixture was stirred at 140° C. for 20 min. The resulting ppt was collected by filtration and washed with excess IPA. The solid was dried under vaccum to give 5-iodo-6-methyl-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (0.282 g, 50.0% yield) as a pale solid. MS (M+H)+ 429.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].OS(O)(=O)=O.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>>[C:16]([CH2:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])([OH:18])=[O:17]
Reactant: COc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Product: COc1ccc(CC(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.4 %

Procedure:
A oven-dried 25 mL three neck round-bottomed flask containing a stirring bar was fitted with a drying tube (CaCl2) and charged with concentrated H2SO4 (12.0 mL). Dichlorovinyl)-5-methoxybenzoic acid (1.69 g, 6.83 mmol) was added portion wise to the stirred solution over 20 min. so that each additional portion was added only after the previous one was completely dissolved. After the addition was complete the reaction was left stirring at room temperature for 2 h and then it was poured onto ice. A precipitate formed and the mixture was stirred until the ice was dissolved. The precipitate was filtered, washed with cold water and dried to give 2-(carboxymethyl)-5-methoxybenzoic acid as an off-white solid (1.18 g, 82%). Spectral data for this compound were consistent with those in the literature. M.p. 175-177° C. (lit. m.p. 180-182° C.); 1H NMR (400 MHz, DMSO-d6): δ=12.36 (br. s, 2H), 7.39 (d, J=2.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4 Hz, J=2.6 Hz, 1H), 3.84 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][Br:35])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(OC(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Oc1cccc(CBr)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 20.83 g (0.098 mol) of 3-methylphenyl benzoate in 280 mL of carbon tetrachloride was added a catalytic amount of benzoyl peroxide, followed by 20.96 g (0.118 mol) of N-bromosuccinimide. The reaction mixture was stirred and heated under reflux overnight. After cooling to room temperature, the solid material was filtered off. The filtrate was washed with 100 mL of water. The organic phase was removed and dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product (31.3 g) was purified by HPLC to give 20.61 g and was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.O.O.Cl.Cl.[NH2:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23].C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[C:22]([CH:21]([NH:20][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)([OH:24])=[O:23]
Reactant: NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 110 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
A mixture of 2,6-dichloro-quinoline-3-carboxylic acid (0.17 g, 0.7 mmol), 2-amino-3-[4-(quinolin-4-ylamino)-phenyl]propionic acid dihydrochloride dihydrate (0.291 g, 0.7 mmol) and K2CO3 (0.507 g, 3.7 mmol) in DMSO (1.5 mL) is stirred at 110° C. temperature for 24 h in a Pierce reaction vial. After cooling the reaction mixture is diluted with water (10 mL) and acidified with 2N aqueous HCl till pH ˜3. The precipitated solid is collected on filter and washed with water to give the title compound (0.3 g, 84%) as yellow solid.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25](=[O:27])[CH3:26]>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:26][C:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)=[O:27])=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: O=C(C=Cc1ccc(-c2ccccc2)cc1)c1ccc2ccccc2c1

Procedure:
Synthesised according to example 1.59.1 using biphenyl-4-carbaldehyde (5.0 g, 29.3 mmol) and 1-(naphthalen-2-yl)ethanone (5.35 g, 29.3 mmol); yellow solid; yield: 7.80 g (79%);
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)[N:7]=1.[O-:17][C:18]#[N:19].[K+]>O>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[N:7]=[C:3]([CH2:2][NH:1][C:18]([NH2:19])=[O:17])[S:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A solution of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g) and potassium cyanate (0.5 g) in water (50 ml) was stirred for 3.5 hours at room temperature. The resulting precipitate was collected by filtration. The precipitate was suspended in water (30 ml) and then a saturated aqueous potassium carbonate solution (20 ml) was added. The mixture was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 2-(diaminomethyleneamino)-4-(2-ureidomethylthiazol-4-yl)thiazole (0.35 g).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NNc1ccc(Br)cc1
Reactant: CCCCCCC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCCc1c(-c2ccccc2)[nH]c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 3. Thus, 4-bromophenylhydrazine, hydrochloride (4.694 g, 21 mmol) was reacted with heptanophenone (3.806 g, 20 mmol) in ethanol (60 ml) to give the product (5.681 g, 16.598 mmol, 79%) as an oily solid. 1H NMR (DMSO-d6) δ 0.79 (t, J=6.8 Hz, 3H), 1.19-1.31 (m, 4H), 1.51-1.57 (m, 2H), 2.75 (t, J=7.8 Hz, 2H), 7.15 (dd, J=2.0, 8.5 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.55-7.58 (m, 2H), 7.64 (d, J=1.8 Hz, 1H), 11.29 (s, 1H); [ESI(−)], m/z 340/342 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[CH2:16][C:15]1([CH3:26])[CH3:25])=[O:12])=[CH:5]2.[CH3:27][O:28][CH2:29][CH:30]=O>C1COCC1.C(Cl)Cl>[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15]([CH3:26])([CH3:25])[C@H:14]2[NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([NH:1][CH2:30][CH2:29][O:28][CH3:27])=[CH:10][CH:9]=3)=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: COCC=O
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(N)ccc2[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCNc1ccc2[nH]c(C(=O)N[C@H]3c4cc(C#N)ccc4CC3(C)C)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a solution of (R)-5-amino-N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-1H-indole-2-carboxamide (66.0 mg, 0.192 mmol) (prepared as described in Example 9) and methoxyacetaldehyde (containing 13% water, 18.0 mg, 0.211 mmol) in 1:1 THF/CH2Cl2 (4 mL) was added NaB(Oac)3H at rt in one portion. The mixture was stirred at rt for 4 hr and the reaction was quenched with saturated with NaHCO3 solution. The mixture was extracted with ethyl acetate (3×20 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The desired product (27.1 mg, 35% yield) was isolated as a pale yellow solid by prep. HPLC. LCMS (M+H)+=345.38. 1H NMR (500 MHz, DMSO-d6) δ: 11.1 (s, 1H), 8.34 (d, J=9.3 Hz, 1H, 7.69 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.03 (s, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.61 (s, 1H), 5.36 (d, J=9.3 Hz, 1H), 5.00 (t, J=5.8 Hz, 1H), 3.51 (t, J=6.0 Hz, 2H), 3.28 (s, 3H), 3.16 (dt, J=11.5, 6.0 Hz, 2H), 2.86 (dd, J=23.0, 16.5 Hz, 2H), 1.20 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]([O:30][CH2:31][CH3:32])[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:36]([C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[NH2:37].C(N(CC)CC)C>CN(C=O)C>[CH2:31]([O:30][C:22]1[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:36]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:37]=2)[CH:21]=1)[CH3:32]
Reactant: NNc1ncccn1
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc2c1OCOC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 105 mg of {2-(8-ethoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF there were added 20.9 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(8-ethoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (46 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7](=[O:13])[C:6]=2[C:14]=1[CH3:15].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:10][C:9]([C:11]3[NH:19][N:18]=[N:17][N:12]=3)=[CH:8][C:7](=[O:13])[C:6]=2[C:14]=1[CH3:15]
Reactant: Cc1cc2oc(C#N)cc(=O)c2c(C)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2oc(-c3nnn[nH]3)cc(=O)c2c(C)c1Cl

Procedure:
A mixture of 23.4 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carbonitrile, 7.8 parts of sodium azide, 6.4 parts of ammonium chloride and 200 parts of N,N-dimethylformamide was stirred and heated on the steam bath for 18 hours. Most of the solvent was then removed by distillation under reduced pressure. A solution of the residue in 400 parts of water was acidified with 20% hydrochloric acid. The precipitated solid was filtered off, washed with water and crystallized from dioxan to give 15.5 parts of 5-(6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-yl) tetrazole as a colourless solid, melting point 246-247°C (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(CC)CC>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
4-Nitrobenzyl chloride (0.086 g, 0.501 mmol) is dissolved in THF (1 mL), and to this solution, is added piperidine (0.059 mL, 0.601 mmol) followed by Et3N (0.210, 1.50 mmol). After stirring the mixture at 50° C. for 5 h, the resulting solution is filtered, and then the solvent is removed via high vacuum to afford the product (0.090 g, 82%); 1H NMR (DMSO-d6) δ 1.25-1.35 (m, 2H), 1.40-1.48 (m, 4H), 2.23-2.32 (m, 4H), 3.47 (s, 2H), 7.50 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H); mass spectrum [(+) ESI], m/z 221 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18]([O:22]CC)[O:19]CC)[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18]([OH:22])[OH:19])[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cn1ccc2ncnc(Oc3ccccc3)c21)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(O)Cn1ccc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
4-Phenoxy-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1.1 g) was dissolved in dichloromethane (4.53 mL)/trifluoroacetic acid (4.53 mL), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The mixture washed with saturated aqueous sodium hydrogen carbonate (80 mL), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (826 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[CH:32]>C(O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][N:18]([CH2:32][C:31]#[CH:30])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCBr
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCN1CCC=C(c2ccc(C(C)(C)CCCCCC)cc2O)C1

Procedure:
A mixture of 1.0 g. (3.33 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine, 539 mg. (3.90 mmoles) of anhydrous potassium carbonate and 395 mg. (3.32 mmoles) of 1-bromo-2-propyne in 23 ml. of ethanol is heated at reflux for 20 hours. The reaction mixture is evaporated and dissolved in 100 ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. The organic extract is washed with two 150 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is crystallized from pentane to yield 161 mg. of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[S:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=1)=[S:29]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C(F)(F)F)c1
Yield: 62.9 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3-trifluoromethylphenyl isothiocyanate (0.82 g, 4.04 mmol). Trituration in hexanes/ethyl acetate gave the product (1.12 g) in two crops; m.p. 177-178° C.