Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([F:37])[CH:17]=1.C(OCC)C>C(#N)C>[F:37][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:36]=[CH:35][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[O:29])[CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
2-Phenylacetyl chloride (100 mg) was dissolved in acetonitrile (2 ml) under a nitrogen atmosphere, and then potassium thiocyanate (126 mg) was added thereto at 50° C., followed by stirring at the same temperature for 1.5 hrs. A solution of 4-(4-amino-2-fluorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (41 mg) in acetonitrile (4 ml) was added thereto, followed by stirring at room temperature for 2.5 hr. The reaction mixture was cooled down to room temperature, and then partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:4). Fractions containing the target compound were concentrated to give a residue, to which a small amount of diethyl ether was added to precipitate crystals. A suspension containing the crystals was diluted with a small amount of hexane. The crystals were filtered off and dried under aeration to provide the titled compound (21.4 mg, 34%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>[Cl-].[Al+3].[Cl-].[Cl-].Cl>[F:9][C:10]([F:18])([F:17])[C:11]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])([OH:12])[C:13]([F:16])([F:15])[F:14]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A 1 L reactor was charged under nitrogen with 200.0 g (1.88 mol) of p-xylene and 12.5 g (0.094 mol/0.05 eq) of aluminum chloride, followed by adjusting the inside temperature to 18° C. Then, 327.7 g (1.97 mol/1.05 eq) of hexafluoroacetone was introduced in a temperature range of 18-25° C. After the introduction, stirring was conducted at room temperature for 3 hr. Then, 200 mL of 10% hydrochloric acid was added. The resulting aqueous layer was extracted two times with 50 mL of chloroform. The resulting organic layers were combined together, followed by removing water with anhydrous magnesium sulfate, filtration, concentration, and vacuum distillation, thereby obtaining 451.3 g of 2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,4-dimethylbenzene represented by the following formula. Upon this, purity was 92%, and yield was 81%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1>O1CCCC1>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([C:33]2[O:5][C:4](=[O:6])[C:3]3[CH:7]=[C:8]([C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:13])[CH3:12])[CH:9]=[CH:10][C:2]=3[N:1]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(c1ccccc1)c1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
To a solution of 2-amino-5-α-cumylbenzoic acid (13.5 g, 0.53 mol, prepared in Example 20) and triethylamine (7.8 g, 0.56 mol) in tetrahydrofuran (200 mL) is added dropwise at room temperature a solution of 4-trifluoromethylbenzoyl chloride (11 g, 0.53 mol). The resulting suspension is stirred at room temperature overnight, then filtered and concentrated to a solid that is then suspended in acetic anhydride and heated to 115° C. for three hours. The resulting solution is cooled and concentrated to an oil. The oil is taken up in ethanol (100 mL) and allowed to stand. The resulting solid formed is coiled and dried to give 15.4 g of the title compound melting at 104–105° C. The structure of the compound is confirmed by 1Hnmr (CDCl3) 500 MHz: δ 1.78 (s, 6H); 7.23 (t, 1H); 7.23 (d, 2H); 7.31 (t, 2H); 7.60 (d, 1H); 7.64 (dd, 1H); 7.78 (d, 2H); 8.26 (d, 1H). 19Fnmr (fluorinated species at −69.57 ppm).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.[N:16]([O-])=[O:17].[Na+].[OH-].[Na+]>CO.C(O)(=O)C.O>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]([N:16]=[O:17])[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: O=N[O-]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CN(N=O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
In a mixture of 34 ml of methanol and 2.07 ml of acetic acid was dissolved 3 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine. Then, a solution of 2.0 g of sodium nitrite in 6.6 ml of water was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous sodium hydroxide solution, concentrated under reduced pressure and extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3.2 g of 3,4-dihydro-2,2-dimethyl-6-nitro-4-nitroso-2H-1,4-benzoxazine.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1ccccc1C(Cl)Cn1ccnc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.64 g of methyl 4-mercaptobenzoate was dissolved in 10.4 ml of dry dimethylformamide, and 424 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 30 minutes. 12 ml of dry dimethylformamide containing 2.15 g of 1-[2-chloro-2-(2-methylphenyl)ethyl]imidazole were added to the resulting solution, and the mixture was heated at a temperature between 60° and 70° C. for 5.5 hours. At the end of this time, the resulting solution was treated and purified by the same procedure as described in Example 1, to give 2.62 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[C:21](Cl)(=O)[C:22](Cl)=O.Cl[CH2:28]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][CH2:28][CH:21]=[CH2:22])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.7 mmol) (compound of Example 9) in dichloromethane (15 mL) was added N,N-dimethylformamide (2 drops) and then in one portion oxalyl chloride (300 μL, 3.4 mmol). The resulting solution was stirred for 24 hours at room temperature, concentrated by rotary evaporation, and allyl alcohol (15 mL) was added to the residue. The mixture was heated at 100° C. for 15 minutes and concentrated by rotary evaporation. The residue was purified by flash chromatography eluting with dichloromethane:methanol (95:5) to give the title compound as a solid (358 mg, 63% yield. 247-249° C.).
Reaction SMILES: C(S([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:35])(=O)=O)(C)C.[OH-].[Na+].C(#N)C>O.C(OCC)(=O)C>[NH2:35][C:8]1[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([C:27]4[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=4[F:33])[NH:19][C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:12][C:11]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(-c4c(F)cccc4F)[nH]c3-c3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2cc(-c3nc(-c4c(F)cccc4F)[nH]c3-c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Yield: 93 %

Procedure:
Stir a mixture of 1-isopropylsulfonyl-2-amino-6-(2-(2,6-difluorophenyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.07 g, 0.142 mmol) and 1.42 mL 1 N sodium hydroxide in 1:1 water:acetonitrile at 60° C. for 1 hour. Cool the mixture to room temperature and dilute with water and ethyl acetate. Extract the aqueous phase with ethyl acetate (3 times). Wash the combined organic phases sequentially with water and saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 2:1 dichloromethane:methanol to provide the title compound in 93% yield. MS(ES+): m/z=388.0 (M+H)+
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Li]CCCC.CCCCC.[NH4+].[Cl-]>O.C1COCC1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:3]#[CH:2]
Reactant: COc1ccncc1C=C(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: C#Cc1cnccc1OC
Temperature: 25 °C

Procedure:
A flask is charged with 3-(2,2-dibromo-vinyl)-4-methoxy-pyridine (3.7 g, 12.63 mmol) and THF (100 mL), and 1.6 M nBuLi in pentane (17.4 mL, 27.79 mmol) is added dropwise at −78° C. The mixture is stirred at −78° C. for 1 h before addition of saturated aqueous NH4Cl (0.5 mL). The mixture is warmed to room temperature and poured into water (100 mL). The mixture is extracted with ethyl acetate and the combined organic phase is dried over Na2SO4. Concentration followed by silica gel flash chromatography eluting with a 0 to 5% methanol-dichloromethane gradient gives 4-methoxy-3-ethynyl-pyridine. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 (s, 1H), 3.96 (s, 3H), 6.82 (d, J=5.8 Hz, 1H), 8.46 (d, J=5.8 Hz, 1H), 8.58 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)Cl

Procedure:
3,6-Dimethyl-2-nitrobenzoic acid in an amount of 9.6 g (51 mmol) was dissolved in 100 ml benzene and then followed by an addition of thionyl chloride in an amount of 8.8 g (74 mmol) and pyridine in an amount of 0.1 lg. The mixture was then heated for 2 hours under reflux, and the solvent therein was distillated out under reduced pressure to obtain 3,6-dimethyl-2-nitrobenzoyl chloride in an amount of 10.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][CH:12]([CH2:14][C:15]([OH:17])=[O:16])[C:11](=[C:18]=[CH2:19])[CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:26]1(I)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][CH:12]3[C:11]([C:18]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH2:19])([O:16][C:15](=[O:17])[CH2:14]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: C=C=C1CC(c2ccc(OC)cc2)OC1CC(=O)O
Reactant: Ic1ccccc1
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: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccccc1)C12CC(c3ccc(OC)cc3)OC1CC(=O)O2
Temperature: 85 °C
Reaction time: 4 h

Procedure:
(5-(4-methoxyphenyl)-3-vinylidene-tetrahydro-furan-2-yl)acetic acid (34 mg, 0.12 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) and K2CO3 (84 mg, 0.61 mmol) were dissolved in 3 mL of dimethylformamide, followed by addition of PhI (68 μL, 0.61 mmol). The solution was stirred for 4 hours at 85° C. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:15, v/v), thus providing products (27 mg, 61%).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:45][N:46]([CH3:51])[CH2:47][C:48](O)=[O:49].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH3:45][N:46]([CH3:51])[CH2:47][C:48]([N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1)=[O:49]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CN(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in chloroform (2 mL), and stirred at room temperature for 1.5 hours after adding N,N-dimethylglycine hydrochloride (Tokyo Chemical Industry Co.; 46.5 mg, 0.333 mmol), diisopropylethylamine (0.146 mL, 0.833 mmol), and (benzotriazol-1-yloxy)tripyrrolizinophosphonium hexafluorophosphate (Watanabe Chemical Industries, Ltd.; 217 mg, 0.417 mmol). The aqueous layer was extracted with chloroform after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 25 (98.9 mg, 86.8%).
Reaction SMILES: [CH2:1]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].B([O-])=O.[Na+]>>[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:8]3[S:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCCCCc1cccs1
Reactant: CCC[C@H]1CC[C@H](c2ccc(CC(=O)Cl)cc2)CC1
Agent: O=B[O-]
Agent: [Na+]
Product: CCCCCc1ccc(C=Cc2ccc([C@H]3CC[C@H](CCC)CC3)cc2)s1

Procedure:
19 g of 2-[4-(trans-4-n-propylcyclohexyl)-styryl]-5-n-pentylthiophene (obtainable by Friedel Crafts acylation of 2-pentylthiophene with 4-(trans-4-n-propylcyclohexyl)-phenylacetyl chloride and reduction of the resulting ketone with sodium boranate to give the alcohol, followed by dehydration) and 5 g of sulfur are heated to 220° for 3 hours. Subsequent working-up by chromatography gives 8.3 g of 2-[4-trans-4-n-propylcyclohexylphenyl]-5-n-pentylthieno[3,2-b]thiophene.
Reaction SMILES: [C:1]1([CH:7]([O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21][Br:22])=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>C(#N)C>[Br-:22].[NH2:25][C:26]1[CH:31]=[CH:30][N+:29]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccncc1
Reactant: BrCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Nc1cc[n+](Cc2ccc(OC(CCc3ccccc3)c3ccccc3)cc2)cc1
Product: [Br-]
Temperature: 25 °C

Procedure:
To a solution of 4-(1,3-diphenyl-1-propoxy)benzyl bromide 6-6 (0.381 g, 1.0 mmol) in acetonitrile (7 ml) was added 4-aminopyridine (6-7) (94 mg, 1.0 mmol) with stirring at room temperature. The mixture was stirred for 3 hrs and the resulting white suspension was filtered. The white solid obtained 6-8, melted at 215°-216.5° C. Recrystallization from acetonitrile raised the melting point to 218.5°-220° C.
Reaction SMILES: C(Cl)CCl.[C:5]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][NH:31][CH3:32].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[CH3:32][N:31]([CH2:30][C:22]1[N:21]([CH3:20])[C:29]2[C:24]([CH:23]=1)=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1-c1ccccc1
Reaction time: 8 h
Yield: 24.7 %

Procedure:
EDC (0.22 g, 1.14 mmole) was added to a solution of 2-biphenylcarboxylic acid (0.22 g, 1.14 mmole), 1-methyl-2-(methylaminomethyl)indole (0.20 g, 1.15 mmole), and HOBt.H2O (0.15 g, 1.11 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) followed by preparative TLC (3% MeOH/CH2Cl2) gave the title compound (0.10 g, 25%) as a light yellow solid: 1H NMR (360 MHz, CDCl3) indicated an approximately 5:1 mixture of amide rotamers; for the major rotamer: δ 7.03-7.58 (m, 13H), 6.19 (s, 1H), 4.50 -5.00 (m, 2H), 3.57 (s, 3H), 2.40 (s, 3H); for the minor rotamer: δ 7.03-7.58 (m, 13H), 6.14 (s, 1H), 4.50-5.00 (m, 2H), 3.38 (s, 3H), 2.76 (s, 3H); MS (ES) m/e 356 (M+H)+. Anal. Calcd for C24H22N2O.0.80H2O: C, 78.15; H, 6.45; N, 7.59. Found: C, 77.96; H, 6.29; N, 7.35.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH:28]=O.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH2:28][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:28][C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:26][C:27]=3[CH:15]=2)[CH2:10][CH2:9]1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)Cc1cc(CNCCCN3CCN(CCCNCc4ccc5c(c4)Cc4ccccc4-5)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-fluorenecarboxaldehyde (1.018 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2 25×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[CH:17]=[C:16]([N:25]2[C:30](=[O:31])[C:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:35][CH:34]=3)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]2[CH3:50])[CH:15]=1>O.C(OCC)(=O)C>[F:13][C:14]1[C:22]2[O:21][C:20]([CH3:23])([CH3:24])[CH2:19][C:18]=2[CH:17]=[C:16]([N:25]2[C:30](=[O:31])[C:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[NH:3][C:4](=[O:7])[O:5][N:46]=4)=[CH:35][CH:34]=3)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]2[CH3:50])[CH:15]=1
Reactant: CCCc1nc(C)n(-c2cc(F)c3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2cc(F)c3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.95 g), sodium hydrogen carbonate (2.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.19 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.49 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.95 g, 71%).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)[N:8]=1.CO.[NH2:21][NH2:22]>O1CCCC1>[NH:21]([C:3]1[N:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)[N:8]=1)[NH2:22]
Reactant: CSc1nncc(-c2cccc(C(F)(F)F)c2)n1
Reactant: NN
Solvent: CO
Solvent: C1CCOC1
Product: NNc1nncc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
To a solution of 22.8 g. of 3-methylthio-5-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine in a mixture of 30 ml. of methanol and 35 ml. of tetrahydrofuran is added 4.84 ml. of 95% hydrazine. The mixture is refluxed for 48 hours, cooled and the solid is collected by filtration giving 3-hydrazino-5-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine as yellow needles.