Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18](=O)[C:17]([CH3:23])([CH3:22])[CH:16]2[C:24]([O-:26])=[O:25])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:27](OC(=O)C)(=O)C>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:20]=[CH:19][S:18][C:17]([CH3:23])([CH3:22])[C@@H:16]2[C:24]([O:26][CH3:27])=[O:25])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCS(=O)C(C)(C)C2C(=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N2C=CSC(C)(C)[C@@H]2C(=O)OC)cc1

Procedure:
A solution of 1.50 g (3.632 mmol) of methyl (3S)A({[4-(2-butynyloxy)-phenyl]sulfonyl)2,2-dimethyl-thiomorpholine-3-carboxylate-1-oxide in 20 mL of acetic anhydride was heated to reflux for 4h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10 ) to provide 0.985 g of methyl(3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-3,4-dihydro-2H-1,4-thiazine-3-carboxylate as a colorless oil. Electrospray Mass Spec 396.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=2)[CH:17]=[CH:18][CH:19]=1)#[N:12]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3C#N)c2)c1
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.33 mmol) in pyridine (2 mL) was added cyclopropanecarbonyl chloride (59 μL, 0.66 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate (50 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (119 mg, 69%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH2:12][NH2:13])[NH:10][N:11]=1.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>C([O-])(O)=O.[Na+].ClC(OC)=O>[CH2:24]([O:23][C:20](=[O:22])[NH:13][CH2:12][C:9]1[NH:10][N:11]=[C:7]([C:6]2[O:5][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:3][C:2]=2[CH3:1])[CH:8]=1)[CH3:25]
Reactant: Cc1nc(-c2ccccc2)oc1-c1cc(CN)[nH]n1
Reactant: CCOC(C)=O
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)NCc1cc(-c2oc(-c3ccccc3)nc2C)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A heterogeneous mixture of the above-prepared C-[5-(4-Methyl-2-phenyl-oxazol-5-yl)-2H-pyrazol-3-yl]-methylamine (31 mg, 0.122 mmole, 1.0 eq) in ethyl acetate (0.5 ml) and 1.0N NaHCO3 (0.5 ml) was treated with excess methyl chloroformate (5 drops) and the mixture stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with water and brine, then dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow solid. Silica gel chromatography eluting with (4:1) hexanes-acetone provided 28 mg (74%) of the title compound as a white solid. 1H NMR (DMSO-d6): δ 2.6 (s, 3H), 3.6 (s, 3H), 4.25 (m, 2H), 6.5 (s, 1H), 7.5 (m, 3H), 7.7 (bm, 1H), 8.0 (m, 2H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:7]>C(#N)C>[N:3]([C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:7])=[C:2]=[S:1]
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)N=C=S)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Potassium thiocyanate (1.08 g) is added to a solution of methyl 4-chlorocarbonylbenzoate (2 g) in acetonitrile (30 ml). After stirring for 1 hour at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The solid obtained is purified by flash chromatography on silica gel (eluent:heptane/ethyl acetate 1:1) in order to produce the expected compound (2.1 g; 95% yield).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C:4](=[O:8])[CH2:5][CH:6]=[CH2:7].O.O.O.O.O.O.O.O.O.[S-2:18].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:7][CH:6]1[CH2:5][C:4](=[O:8])[CH2:3][CH:2]([CH3:1])[S:18]1
Reactant: [S-2]
Reactant: C=CCC(=O)CC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(=O)CC(C)S1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.5 %

Procedure:
1,6-Heptadien-4-one (0.50 g, 4.54 mmol) was dissolved in toluene (8 mL) and water (4 mL). Sodium sulfide nonahydrate (1.09 g, 4.54 mmol) was dissolved in water (4 mL) and added to the solution above and stirred at room temp. After 5 h, the aqueous layer was saturated with potassium carbonate and extracted with diethyl ether. The combined organics were washed with brine, dried MgSO4, and concentrated. The crude compound was purified on a Combiflash silica column with 0-10% EtOAc/hexanes to give 0.193 g (29%) of the title compound.
Reaction SMILES: [NH3:1].[C:2]([NH:5][C:6]1[C:7](=[O:20])[C:8]2[C:13]([C:14](=[O:17])[C:15]=1Br)=[CH:12][C:11]([CH3:18])=[C:10]([CH3:19])[CH:9]=2)(=[O:4])[CH3:3]>[N+](C1C=CC=CC=1)([O-])=O>[C:2]([NH:5][C:6]1[C:7](=[O:20])[C:8]2[C:13]([C:14](=[O:17])[C:15]=1[NH2:1])=[CH:12][C:11]([CH3:18])=[C:10]([CH3:19])[CH:9]=2)(=[O:4])[CH3:3]
Reactant: CC(=O)NC1=C(Br)C(=O)c2cc(C)c(C)cc2C1=O
Reactant: N
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)NC1=C(N)C(=O)c2cc(C)c(C)cc2C1=O
Temperature: 216 °C

Procedure:
Dry ammonia was passed through a stirred refluxing solution of 2-acetamido-3-bromo-6,7-dimethyl-1,4-naphthoquinone (7.5 g) in nitrobenzene (50 ml) for 1 hr. and the mixture cooled. The red solid which separated was filtered off, washed well with ether-petrol and then water to give 4.46 g. (77%) of material of mp 212°-216° C. Recrystallisation from ethanol raised the melting point to 216° C., ν max(mull), 3400, 3270, 1675, 1665, 1630 cm-1. δ (DMSO) 2.05 (3H,s); 2.35 (6H,s); 6.64 (2H, exchangeable s); 7.71(2H,s); 9.00 (1H, exchangeable s.) (Found; C, 65.07; H, 5.43; N, 10.66; C14H14N2O3 requires; C, 65.10; H, 5.46; N, 10.85%).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:21].[Na+]>CC(C)=O>[I:21][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 40.5 g. (0.1 moles) of ethyl α-bromo-2'-chloro-4-biphenylylacetate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-2'-chloro-4-biphenylylacetate.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=O)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50](O)=[O:51]>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][C:32]([CH:50]([OH:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][NH2:35])=[O:34])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: NCCOCCOCCOCCOCCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCC(=O)C(O)CCOCCOCCOCCOCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 155.1 %

Procedure:
The mixture of pentafluorophenyl ester of 4-(Cholest-5-en-3β-yloxy)butanoic acid (121 mg, 0.19 mmol) and 15-amino-4,7,10,13-tetraoxapentadecanoic acid (104 mg, 0.39 mmol) was dried in an apparatus equipped with septum for 4 h at room temperature and 0.1 Pa. The apparatus was flushed with argon (2×) and then dry N,N-dimethylformamide (4 ml) and N-ethyldiisopropylamine (1 ml) were added through the septum and the mixture was stirred at room temperature for 16 h. Flash chromatography of the crude reaction mixture on silica gel column (100 ml) in toluene-ethyl acetate (gradient: 0-40% ethyl acetate, 10 ml/min, 160 min) gave [4-(Cholest-5-en-3β-yloxy)butanoyl]-15-amino-4,7,10,13-tetraoxapentadecanol acid (general formula X, where n3=3 and n4=3; 208 mg, 88%). 1H NMR (400 MHz, Acetone) δ ppm: 3.71 t, J=6.32 Hz, 2H (CH2-3); 3.55-3.60 m, 14H (7×CH2—O); 3.51 t, J=5.60 Hz, 2H (CH2-14); 3.45 t, J=6.32 Hz, 2H (CH2-4′); 3.34 q, J=5.73 Hz, 1H (CH-3″); 2.53 t, J=6.32 Hz, 2H (CH2-2); 2.34 ddd, J=13.20, 4.70, 2.10 Hz, 1H (H-4a″); 2.24 t, J=7.45 Hz, 2H (CH2-2′); 1.82-2.17 m, 5H (cholesteryl); 1.76-1.82 m, 2H (CH2-3′); 1.01 s, 3H (CH3-19″); 0.94 d, J=6.57 Hz, 3H (CH3-21″); 0.87 d, J=1.26 Hz, 3H (CH3-26″); 0.86 d, J=1.52 Hz, 3H (CH3-27″); 0.81-1.66 m, 34H (cholesteryl); 0.71 s, 3H (CH3-18″); for C42H73NO8—H HR-MS, calculated m/z: 720.5409. found m/z: 720.5407.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](=O)([O-])[O-:17].[K+].[K+]>CN(C=O)C>[CH2:1]([O:17][CH2:16][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 23 °C

Procedure:
A solution of benzyl bromide (128 mg, 0.75 mmol), phenol compound 40 (131.5 mg, 0.50 mmol), and potassium carbonate (138 mg, 1.00 mmol) in DMF (3.0 mL) was heated to 60° C. for 1.5 h. After cooling to 23° C., the solution was filtered, concentrated in vacuo, and purified by silica gel chromatography (1:1 EtOAc/hexanes) to give benzyl ether compound 49 (132.5 mg, 75%) as a white solid. mp=124-125° C.; 1H NMR (CDCl3) δ 7.67 (s, 1H), 7.49 (s, 1H), 7.40 (m, 6H), 6.0-5.8 (2 br s, 2H), 5.08 (s, 2H); IR (KBr pellet) 3369, 3192, 1660, 1564 cm−1; Anal. (C14H12INO2) C, H, N.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:37]1(=O)[NH:42][CH2:41][CH2:40][N:39]2[CH2:43][CH2:44][CH2:45][C@@H:38]12.CNCCNC.ClCCl.[O:56]1CCOC[CH2:57]1>[Cu]I>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][CH2:40][N:39]4[CH2:43][CH2:44][CH2:45][C@H:38]4[C@@H:37]3[CH2:57][OH:56])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1NCCN2CCC[C@@H]12
Reactant: C1COCCO1
Agent: [Cu]I
Agent: CNCCNC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@H]3[C@@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A suspension of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (100 mg), (8aS)-hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (D76, 79 mg, 3 eq), CuI (72 mg, 2 eq), N,N′-Dimethylethylenediamine (40 μl, 2 eq) and CsCO3(122.4 mg, 2 eq) in dioxane (3 ml) was heated in a sealed tube at 80° C. for 4 hrs and at 120° C. overnight. The reaction mixture was taken up with dichloromethane and it was washed with NH4Cl aq. The organic phase was evaporated to dryness and the crude was purified by chromatography (silica cartridge, cyclohexane:EtOAc 1:1 to 0:1) to give the title compound (39 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](Cl)=[N:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C>[CH2:1]([N:4]1[C:12]2[C:11]3=[N:20][N:21]=[N:22][N:10]3[C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCn1cnc2c1c(Cl)nc(=O)n2CCCCC
Agent: [Na+]
Solvent: CCO
Product: C=CCn1cnc2c1c1nnnn1c(=O)n2CCCCC
Yield: 22.7 %

Procedure:
A mixture of 7-allyl-6-chloro-3-pentyl-3,7-dihydro-2H-purin-2-one (0.65 g, 2.3 mmol) and sodium azide (0.98 g, 15 mmol) in ethanol (20 mL) was refluxed overnight. The reaction mixture was concentrated under vacuum. The residue was diluted with water and EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative LCMS to provide the desired product as a white powder (0.15 g, 22.6%). LCMS calculated for C13H18N7O (M+H): 288.2. found: 288.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[N:7]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)=[N:9][N:10]=3)[N:7]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: Oc1ccc(Cc2nnc3ccc(Cl)nn23)cc1
Reactant: c1c[nH]cn1
Product: Oc1ccc(Cc2nnc3ccc(-n4ccnc4)nn23)cc1

Procedure:
The title compound was prepared from 4-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-phenol (Example 45: step a) and imidazole as described in Example 43. 1H-NMR (CD3OD): δ 9.78 (1H, t, J=1.3 Hz), 8.54 (1H, d, J=9.9 Hz), 8.38 (1H, t, J=1.8 Hz), 7.97 (1H, d, J=9.9 Hz), 7.83 (1H, dd, J=1.3, 1.8 Hz), 7.23 (2H, d, J=8.6 Hz), 6.72 (2H, d, J=8.6 Hz), 4.53 (s, 2H). ESI-MS (m/z): Calcd. for C15H12N6O: 292.1; found: 293.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Na].[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([NH:16][NH2:17])=O>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:2]=[C:14]([C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([Cl:10])[CH:12]=2)[NH:16][N:17]=1
Reactant: N#Cc1ccccn1
Reactant: NNC(=O)c1cccc(Cl)c1
Agent: [Na]
Solvent: CO
Product: Clc1cccc(-c2nc(-c3ccccn3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Using the procedures of Browne et al., Aust. J. Chem., (1975) 28:2543-2546, a solution of 2-cyanopyridine (0.1 mL, 1.00 mmol) in methanol (5 mL) was treated with sodium metal (6.9 mg, 0.30 mmol) and stirred for at ambient temperature for 1 hour. After this time, a solution of 3-chlorobenzhyrazide (0.17 g, 1.0 mmol) in methanol (5 mL) was added and the resulting solution heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the resulting yellow solid (100 mg) dissolved in toluene (2 mL). The mixture was heated at 175° C. for 3 hours and then stirred overnight at ambient temperature. Evaporation of the solvent in vacuo and silica gel chromatography using 1% methanol in dichloromethane afforded 29 mg (11%) of 3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-triazole as an off-white solid.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:14][C:15]1[CH:16]=[C:17]([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>ClCCl>[F:37][C:33]1[CH:32]=[C:31]([C:21]2([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)[CH:29]3[CH:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CN(C(=O)Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A solution of (2-methoxyphenyl)acetic acid (0.46 g) in dry dichloromethane (15 cc) is cooled to 0° C., then treated with N,N'-carbonyldiimidazole (0.45 g) and stirred for 1 hour at 0° C. A solution of 7,7-bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dichloromethane (20 cc) is added dropwise. The reaction mixture is stirred for 3 hours at 25° C. and then washed with water (2×50 cc) and with saturated sodium chloride solution (50 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2.2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70:30 by volume) and collecting 15-cc fractions. Fractions 4 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa), and the product obtained is recrystallized in acetonitrile. The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-(phenylacetyl)perhydro-4-isoindolone (0.76 g) is obtained. M.p. 194° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:23]([O:27][C:28]1[CH:34]=[CH:33][C:31](O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]>O1CCCC1.C(N(CC)CC)C>[CH2:23]([O:27][C:28]1[CH:34]=[CH:33][C:31]([O:19][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:22][CH:21]=2)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.1 g of 4-(6-methacryloyloxyhexyloxy)benzoic acid were converted to the acid chloride in a manner similar to example 6. This substance was taken up in 100 ml of tetrahydrofuran (THF) and added dropwise at 0° to 5° C. to a stirred solution of 3.3 g of hydroquinone monobutyl ether in 100 ml of THF and 4 ml of triethylamine. The mixture was stirred for a further 3 hours at room temperature and the triethylamine hydrochloride was then filtered out. The filtrate was evaporated to dryness and the residue dissolved in 50 ml of dichloromethane. The solution was washed several times with water, dried with sodium sulphate and the solvent then distilled off. The crude product so obtained was purified by column chromatography and recrystallisation from n-hexane.
Reaction SMILES: [Br:1][C:2]1([C:5]([NH:7][CH2:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13])=O)[CH2:4][CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1([C:5]2[S:16][C:9]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCC(=O)CNC(=O)C1(Br)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCc1cnc(C2(Br)CC2)s1
Yield: 193.4 %

Procedure:
500 mg of amide 86 and 212 mg of phosphorus pentasulfide are heated in 2 ml of dioxane for 25 minutes to 100° C. and, after cooling, poured into dilute sodium hydroxide solution. After extraction with ethyl acetate and drying on sodium sulfate, it is concentrated by evaporation, and the oily residue is chromatographed on silica gel with ethyl acetate/hexane. 240 mg of title compound 89 is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([OH:17])=O)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C@H:47]([NH2:49])[CH3:48])=[CH:43][CH:42]=1>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:17])[NH:49][C@@H:47]([C:44]2[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=2)[CH3:48])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(C(=O)O)n2c1COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)n2c1COCC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester (Comp. No. 5a) (6.09 g, 25.5 mmol) in dimethylformamide (60 ml) was added 1-hydroxybenzotriazole (3.785 g, 0.028 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.37 g, 28 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(4-fluoro-phenyl)ethylamine (3.9 g, 28 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water to give 9.0 g (98%) of 6-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH3:29][N:30]([CH3:36])[C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][N:30]([CH3:36])[C@@H:31]1[CH2:35][CH2:34][N:33]([CH2:22][CH2:21][C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:11]4[N:12]5[C:4](=[CH:3][CH:2]=[N:1]5)[N:5]=[C:6]5[C:10]=4[CH2:9][CH2:8][CH2:7]5)=[CH:28][C:17]=3[CH:18]=2)[CH2:32]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Reactant: CN(C)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)[C@@H]1CCN(CCc2cc3cc(-c4c5c(nc6ccnn46)CCC5)ccc3o2)C1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) described above was dissolved in acetonitrile (2 ml) followed by addition of 3-(R)-dimethylaminopyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give 8-{2-[2-(3-(R)-Dimethylamino-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-6,7-dihydro-5H-1,4,8a-triaza-s-indacene.