Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][C:5]1[C:6]([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:62][C@H:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][CH2:64]1>ClCCl>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][C:5]1[C:6]([NH:27][C:28](=[O:33])[C:29]([F:30])([F:32])[F:31])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:62][C@H:63]3[C:71]4[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=4)[CH2:65][CH2:64]3)=[O:24])=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=C(O)c1ccc(-c2c(NC(=O)C(F)(F)F)c(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H]1CCc2ccccc21)c1ccc(-c2c(NC(=O)C(F)(F)F)c(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the 2.0 ml dichloromethane solution containing the acid (G, 4-{(9aS)-2-(2,4-difluorobenzyl)-5-oxo-3-[(trifluoroacetyl)amino]-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}benzoic acid, 956 mg, 1.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (691 mg, 3.6 mmol) and 1-hydroxybenzotriazole hydrate, 480 mg (R)-(−)-1-aminoindan (3.6 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. Diluted with dichloromethane. Washed with water and brine subsequently. Dried with sodium sulfate. Upon the removal of the solvent, the residue was purified with flash chromatography. 320 mg of the title compound as a light yellowish solid was obtained. NMR (400 MHz, CDCl3) δ 7.95 (m, 2H), 7.32 (m, 5H), 6.95 (m, 4 m), 5.62 (m, 1H), 4.59 (m, 1H), 4.15 (m, 1H), 3.55 (s, 2H), 3.15 (m, 1H), 3.06 (m, 1H), 2.90 (m, 1H), 2.58 (m, 1H), 2.32 (m, 2H), 2.02 (m, 1H), 1.25 (m, 1H) ppm. ESI-MS m/z 647 (M+H)+, 645 (M−H)−.
Reaction SMILES: [C:1]1([CH3:11])[C:2]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:10][O:9][C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:11][Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 37.4 %

Procedure:
A mixture of methyl o-toluate (13.5 g, 89.9 mmol), NBS (17.6 g, 98.9 mmol), and benzoyl peroxide (50 mg, 0.2 mmol) in carbon tetrachloride (250 mL) was heated at reflux over the weekend. The reaction mixture was allowed to cool, and it was then filtered. The solvents were evaporated under reduced pressure and the residue was purified by chromatography, eluting with 3% ethyl acetate/hexanes to give 2-bromomethyl-benzoic acid methyl ester (7.7 g, 37%) as a white solid. 1HNMR (CDCl3): δ 7.97 (dd, J=1.5 Hz, 8.0 Hz, 1H), 7.49 (m, 2H), 7.38 (dt, J=1.5 Hz, 8.0 Hz, 1H), 4.96 (s, 2H), 3.94 (s, 3H). MS (APCI+): 231 (100), 229 (93).
Reaction SMILES: [CH2:1]([C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)S(OC)(=O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C@H:35]2[CH2:40][NH:39][CH2:38][CH2:37][NH:36]2)[CH:32]=[CH:33][CH:34]=1.N1C=CC=[CH:43][CH:42]=1>C(Cl)Cl>[CH2:1]([C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([N:39]3[CH2:38][CH2:37][NH:36][C@@H:35]([CH2:31][CH2:32][C:33]4[CH:43]=[CH:42][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=4)[CH2:40]3)[C:5]=2[N:4]=1)[CH3:2]
Reactant: COc1cccc([C@H]2CNCCN2)c1
Reactant: CCc1nc2c(s1)Nc1ccccc1NC2=S
Reactant: c1ccncc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(OC)c2)C1
Temperature: 35 °C

Procedure:
By using a method similar to the Example 501, using a suspension of 2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (3.4 g, 13.0 mmol) in 35 mL CH2Cl2, add methyl trifluoromethanesulfonate (4.2 g, 26.0 mmol) overnight, LC-MS showed still had 50% of starting material, added another 0.1 mL of methyl trifluoromethanesulfonate, and heated to 35° C. for 1 h. Concentrate the reaction mixture under reduced pressure, give a red-brown solid. Dissolve the solid in 32.5 mL of pyridine to make 0.4 M of solution. Take 6.25 mL of the solution (2.5 mmol), mix with (S)-2-(3-methoxy-phenyl)-piperazine (550 mg, 2.5 mmol) and heat to 100° C. for 3 hours. Cool the reaction to RT, concentrate down to a residue, which purify by flash chromatography on silica gel, gradient 100% CH2Cl2 to 100% mixed solvent of (CH2Cl2: 2N NH3/MeOH=20:1) over 55 min. give 306 mg of the title compound. Mass spectrum (APCI) (m/e): C25H29N5OS, Cacl. Mass: 447.21, Found: 448.2 (M+1); 1H NMR (300 MHz, CDCl3) δ ppm: 7.21–7.16 (m, 1H), 7.08–6.96 (m, 2H), 6.91–6.86 (m, 1H), 6.80–6.71 (m, 3H), 6.65–6.64 (m, 1H), 5.40 (br, 1H), 4.35–4.25 (m, 2H), 3.78 (s, 3H), 3.16–2.69 (m, 10H), 1.79–1.76 (m, 2H), 1.29 (t, 3H, J=7.7 Hz).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH2:19][C:18]2=O)[CH:12]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:18]1[N:17]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]=1[CH:3]=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2cccnc2N1c1cccnc1
Reactant: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1c(Cl)n(-c2cccnc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
An ice-acetone cooled solution of anhydrous dimethylformamide (0.71 mL, 9.2 mmol) and anhydrous dichloromethane (2 mL) under a N2 atmosphere is treated drop-wise with phosphorus oxychloride (0.93 mL, 10 mmol). The resulting yellowish mixture is continued to stir for 40 mins to give a cloudy mixture. A solution of 1-pyridin-3-yl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (370 mg, 1.75 mmol) and pyridine (0.30 mL, 3.7 mmol) in dichloromethane (1 mL) is added drop-wise over 20 minutes to form a red mixture. The reaction is allowed to warm slowly to room temperature over 1 hour, and stirred at room temperature for 24 hours. The red reaction mixture is concentrated, and the residue is treated with phosphorus oxychloride (10 mL) and the mixture heated in an oil bath at 110° C. for 3 hours. After concentration of the red mixture, the residue is treated with ice water, and treated with saturated aqueous sodium hydrogen carbonate solution until the effervescence ceases. The mixture is extracted with 5 portions of dichloromethane, the combined extracts are dried over magnesium sulfate, filtered and evaporated to leave a brown solid. The residue is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated, and the residue is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane. After trituration with heptane 36 mg of 2-chloro-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde is obtained as a fluffy cream powder. A further 11 mg of product is obtained by purifying the heptane supernatant by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (99:1) increasing to ethyl acetate. Total yield, 47 mg, 10% yield. MS: m/e 258/260 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(N(CC)CC)C.[C:23]([S:31][CH2:32][CH2:33][C:34](Cl)=[O:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CC(C)=O.CCOCC>[C:23]([S:31][CH2:32][CH2:33][C:34]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)CCSC(=O)c1ccccc1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(SCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1

Procedure:
11.3 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 13.2 g of triethylamine are dissolved in 200 ml of dehydrated acetone and 11.7 g of S-benzoyl-3-mercaptopropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour. 4 N Hydrochloric acid in ether is added to this mixture and the precipitate is filtered. The filtrate is concentrated in vacuo and the obtained oil is dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 12 g (58%), mp. 100.5°-101° C. (dec.) (ethyl acetatebenzene), [α]D26 +130.8° (c=1.0, methanol).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C#N)cc1
Temperature: 110 °C
Yield: 94 %

Procedure:
To the mixture of 4-bromobenzonitrile (2.6 g, 14.28 mmol), Pd(OAc)2 (0.064 g, 0.286 mmol) and tri-o-tolylphosphine (0.261 g, 0.857 mmol) in dry DMF (20 mL) was added ethyl 2-propenoate (2.282 mL, 21.43 mmol) and TEA (3.98 mL, 28.6 mmol). It was heated at 110° C. for 1 h. Purification via a flash column chromatography then provided the title compound as a white solid (2.7 g, 92% yield). LCMS: rt=3.03 Min, [M+H+]=202.0
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.[C:19]([O-:22])([O-])=[O:20].[Cs+].[Cs+].CO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([C:9]#[C:8][C:7]2[C:2]([C:14]3[CH:15]=[CH:10][C:11]([C:19]([OH:22])=[O:20])=[N:12][CH:13]=3)=[N:3][CH:4]=[N:5][C:6]=2[CH2:17][CH3:18])=[CH:15][CH:14]=1
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: COCCOC
Solvent: CO
Product: CCc1ncnc(-c2ccc(C(=O)O)nc2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C

Procedure:
The title compound is synthesized in analogy to general procedure GP4 starting from 1.2 g (4.63 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 1.0 g (5.6 mmol) 4-methoxycarbonyl-3-pyridyl boronic acid, 163 mg (0.23 mmol) bis-(triphenylphoshine)palladium(II) chloride, 7.0 mL (13.9 mmol) of an aqueous 2 M Cs2CO3 and 2 mL MeOH in 10 mL DME. The reaction mixture is stirred over night at 80° C. The reaction mixture is poured on water and washed with DCM. Aqueous 1 M HCl is added to the aqueous phase until pH 5 is reached. The precipitated product is filtered off and washed with water and methanol. After drying 290 mg (13%) of the desired product are obtained a solid material which is used for the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:13][C:12]=12.N1[CH2:35][CH:34](C2C=CC(C(NCC3C=CN4C=CN=C4C=3)=O)=CC=2)[CH2:33]1>>[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:21]=[CH:22][C:23]([CH:26]4[CH2:30][CH2:29][N:28]([S:4]([C:2]5[CH:3]=[CH:35][CH:34]=[CH:33][CH:1]=5)(=[O:6])=[O:5])[CH2:27]4)=[CH:24][CH:25]=3)=[CH:13][C:12]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNC2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(S(=O)(=O)c3ccccc3)C2)cc1

Procedure:
The title compound was prepared as described in Example 557C, substituting benzene sulfonyl chloride for propane-2-sulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(pyrrolidin-3-yl)benzamide for 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (t, J=5.9 Hz, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 7.87 (m, 3H), 7.81 (m, 2H), 7.74 (m, 1H), 7.66 (m, 2H), 7.51 (d, J=1.2 Hz, 1H), 7.37 (m, 1H), 7.25 (m, 2H), 6.84 (dd, J=6.9, 1.7 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 3.72 (dd, J=9.8, 7.5 Hz, 1H), 3.46 (m, 1H), 3.26 (m, 2H), 3.11 (m, 1H), 2.17 (m, 1H), 1.78 (m, 1H); MS (ESI(+)) m/e 461 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2Cl)(=[O:3])[NH2:2].[F:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[N:25]([CH3:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:27].[H-].[Na+].O>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:24][C:22]1[CH:21]=[CH:20][C:19]([N:25]([CH3:36])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[C:18]([F:17])[CH:23]=1)(=[O:3])[NH2:2]
Reactant: CN(C(=O)Nc1ccc(F)cc1)c1ccc(O)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N(C)C(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C(N)=O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
6-Carbamoyl-4-chloro-7-methoxyquinoline (41 mg, 0.1744 mmol) and N-(2-fluoro-4-hydroxyphenyl)-N′-(4-fluorophenyl)-N-methylurea (57 mg, 0.2048 mmol) were dissolved in dimethylsulfoxide (1.0 ml), and then sodium hydride (8.4 mg, 0.2093 mmol) was added and the mixture was heated and stirred at 85° C. for 30 minutes. After cooling the reaction solution to room temperature, water was added and the precipitated crystals were filtered out. The crystals were then suspended in acetone: diethyl ether=1:2 and refiltered out, washed with diethyl ether and dried by aspiration to obtain the title compound (46 mg, 0.0961 mmol, 55.13%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]([OH:49])([C:47]#[CH:48])[CH3:46]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:48]#[C:47][C:45]([OH:49])([CH3:46])[CH3:44])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)CC1COc2ccc(Br)cc2-c2nc(C(=O)OC)sc21
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(=O)OC)sc21
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To a stirred mixture of 9-Bromo-4-methoxycarbonylmethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (90 mg, 0.22 mmol) in TEA (5 mL) and DMF (1 mL) were added Pd(PPh3)Cl2 (15 mg, 0.021 mmol), PPh3 (17.2 mg, 0.065 mmol), CuI (8.3 mg, 0.043 mmol) and 2-methylbut-3-yn-2-ol (92 mg, 1.09 mmol). The reaction mixture was degassed with N2 and heated to 80° C. in a microwave reactor for 1.5 h. Then the mixture was cooled to room temperature, EtOAc was added. The mixture was filtered through Celite. The filtrate was washed with saturated brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-methoxycarbonylmethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (70 mg, 77%) as a light yellow solid. LC-MS (ESI & APCI): 416.7 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1.[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23][CH2:24]2)=[CH:5]1
Reactant: BrCCC1=CCc2ccccc21
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(NC1CCN(CCC2=CCc3ccccc32)CC1)c1ccccc1

Procedure:
3-(2-Bromoethyl)indene (1.12 g.), 4-benzamidopiperidine (1.02 g.) and potassium carbonate (1.38 g.) were heated under reflux in isopropanol (25 ml.) for 24 hours. The mixture was filtered and the filtrate was evaporated. Trituration of the residue with ether gave a solid which was recrystallised twice from aqueous ethanol to provide the title compound, m.p. 148°-149° C. (Found: C, 79.7; H, 7.6; N, 8.0. C23H26N2O requires C, 79.7; H, 7.6; N, 8.1%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[Li][AlH][SeH:12]>>[CH:1]([NH:4][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[Se:12])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=NC(C)C
Reactant: [Li][AlH][SeH]
Product: CC(C)NC(=[Se])NC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
N,N′-diisopropylcarbodiimide (0.15 mL, 1.0 mmol) was added to the solution of LiAlHSeH (1.0 mmol) prepared as described above in Example One. The reaction mixture was stirred at 0° C. for one hour. The mixture was extracted with diethyl ether and washed with saturated NaCl solution. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel with dichloromethane:n-hexane (40:1) to give 0.13 grams (62%) N,N′-diisopropylselenourea as a white crystal; mp 142.6–148.2° C.; C7H16N2Se; IR (KBr) 1515, 1570, 3195, 3246 cm−1; 1H NMR (CDCl3) δ 1.19 (12H, d, J=6.4 Hz, CH3), 4.21 (2H, br s), 6.10 (2H, br s); 13C NMR (CDCl3) δ 22.4, 47.9,176.2; MS (EI): m/z=208 [M+]; HRMS: m/z=208.0478 calcd for C7H16N2Se, found 208.0503.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=CC=CC=3)[S:43]CC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:43][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCSc3ccccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCSc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.36, 7.32, 7.29, 7.20, 7.07, 5.49, 4.64, 3.23, 3.02, 2.72, 2.64, 2.53, 2.20, 1.27, 1.22; 13C NMR (100 MHz, CDCl3) δ 151.42, 150.26, 140.63, 137.74, 137.67, 135.29, 134.57, 134.22, 132.88, 131.23, 129.81, 129.11, 128.53, 127.52, 127.28, 124.87, 48.48, 27.58, 26.34, 23.18, 23.11, 13.30, 11.64; HRMS (FAB) calcd for C23H23Cl2N3S+H 444.1068, found 444.1055.
Reaction SMILES: Cl[CH2:2][C:3]([C:7]1([Cl:10])[CH2:9][CH2:8]1)([OH:6])[C:4]#[CH:5].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O1CCCC1>[Cl:10][C:7]1([C:3]([OH:6])([CH2:2][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[C:4]#[CH:5])[CH2:9][CH2:8]1.[CH:2]#[CH:3]
Reactant: C#CC(O)(CCl)C1(Cl)CC1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C#C
Product: C#CC(O)(Cn1cncn1)C1(Cl)CC1
Yield: 46 %
Yield: 400 %

Procedure:
A mixture of 18.0 g (0.1 mol) of 4-chloro-3-(1-chlorocyclopropyl)-3-hydroxy-1-butine, 13.9 g (0.201 mol) of 1,2,4-triazole and 55.5 g (0.402 mol) of potassium carbonate in 250 ml of absolute acetone is refluxed for 2 hours. The mixture is subsequently concentrated by stripping off the diluent under reduced pressure, and the concentrate is then treated with water. The resulting mixture is extracted using methylene chloride. The combined organic phases are dried and concentrated under reduced pressure. The residue which remains is chromatographed on silica gel using a mixture of cyclohexane/ethyl acetate = 1:1 as the eluent. After the eluate has been evaporated, 9.7 g (46% of theory)of 3-(1-chloro-1cyclopropyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)-but-1-ine are obtained in the form of a solid substance of melting point 70°-72° C. ##STR33## To a solution of 5.2 g (0.2 mol) of acetylene in 200 ml of absolute tetrahydrofuran there are added dropwise at 70° C. 80 ml (0.2 mol) of a 23% strength butyllithium solution in hexane. After 10 minutes, a solution of 20 g (0.13 mol) of 2-chloro-1-(1-chlorocyclopropyl-1-)ethanone in 100 ml of absolute tetrahydrofuran is added. Stirring is continued for 2 hours at -70° C. The reaction is then stopped by dropwise addition of the mixture of 20 ml of methanol and 20 ml of acetic acid. The solvent is stripped off in vacuo and the remaining mixture is dissolved in dichloromethane and then extracted several times by shaking with saturated aqueous ammonium chloride solution. After the organic phase has been dried and distilled off, 24.4 g of crude product with a content of 83.1% of 4-chloro-3-(1-chloro-cyclopropyl)-3-hydroxy1-butine are obtained.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:35][C:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH3:36]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CC(C)(N)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 2-amino-2-(2-pyridyl)-propane (47 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 50 mg of the title compound as a yellow solid.