Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>O1CCOCC1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:17]([NH:16][CH2:14][CH3:15])=[O:18])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN=C=O
Reactant: COc1cc2sc(N)nc2cc1Br
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)c(OC)cc2s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-6-methoxybenzo[d]thiazol-2-amine V (2.0 g, 7.72 mmol) in 1,4-dioxane (20.0 mL) was added ethylisocyanate (3.0 mL, 38.60 mmol) and heated the resulting reaction mixture to 80° C. for 16 h. After the completion of the reaction (TLC monitoring), 1,4-dioxane was distilled off followed by co-distillation with n-hexane (2 times). The residue was then stirred with water at 90° C. for 2 h followed by filtration to obtain the desired product that was further washed with hot water and then dried. The residue was finally washed with ether to obtain the desired product (2.10 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 1.07 (t, J=7.20 Hz, 3H), 3.17 (quintet, J=6.80 Hz, 2H), 3.86 (s, 3H), 6.65 (br s, 1H), 7.68 (s, 1H), 7.80 (s, 1H) and 10.67 (br s, 1H). MS: 330.08 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>CCOC(C)=O.C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]=1[CH3:11]
Reactant: ClCc1ccccn1
Reactant: COC(=O)c1ccc(O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2ccccn2)cc1C
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To 0.85 g of 4-hydroxy-2-methyl benzoic acid methyl ester were added 12 mL of acetonitrile, 2.12 g of K2CO3 and 0.84 g of 2-(chloromethyl)pyridine hydrochloride, and the mixture was stirred at 90° C. for 4 hours. The reaction mixture was allowed to cool back to room temperature and neutralized by the addition of 5% hydrochloric acid. To this, 150 mL of AcOEt was added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt system) to give 1.18 g of the title compound (89% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])(=O)=O)=CC=1.[ClH:42].Cl.C(O)(C)C>>[ClH:42].[F:38][C:37]([F:39])([F:40])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][CH2:29][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2C(F)(F)F)cc1
Agent: Cl
Solvent: CC(C)O
Product: O=C(N[C@H]1CCN(CCc2ccccc2C(F)(F)F)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(2-trifluoromethylphenyl)ethyl p-toluenesulfonate (0.69 g) were reacted under the same conditions as in Example 1. After the same post-treatment as in Example 1, the obtained compound was converted to hydrochloride with 30% hydrochloric acid-isopropanol to give (S)-N-(1-(2-(2-trifluoromethylphenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide hydrochloride 1 hydrate (0.44 g), melting point 127-128° C.
Reaction SMILES: [CH2:1]([O:14][C:15](Cl)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH:18]1[CH:23]=[C:22]2[NH:24][C:25]([C:27]3[NH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[N:26][C:21]2=[CH:20][CH:19]=1>>[CH2:1]([O:14][C:15]([N:35]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=[C:27]1[C:25]1[N:24]([C:15]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:16])[C:22]2[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=2[N:26]=1)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCOC(=O)Cl
Reactant: c1ccc2[nH]c(-c3nc4ccccc4[nH]3)nc2c1
Product: CCCCCCCCCCCCCOC(=O)n1c(-c2nc3ccccc3n2C(=O)OCCCCCCCCCCCCC)nc2ccccc21

Procedure:
Following the procedure of Example 2, tridecylchloroformate was reacted with 2,2'-bibenzimidazole to give 1,1'-bis(tridecyloxycarbonyl)-2,2'- bibenzimidazole in 86% purity.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]([CH2:11][C:12]#[CH:13])[CH2:9][CH3:10])[CH3:7].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].Cl>CCCCCC.O1CCCC1>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])([CH3:20])[C:13]#[C:12][CH2:11][N:8]([CH2:9][CH3:10])[CH2:6][CH3:7]
Reactant: C#CCN(CC)CC
Reactant: CC(=O)CCCCCl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)CC#CC(C)(O)CCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.37 ml (19.8 mmol) of a 1.6 M solution of n-butyllithium in n-hexane were slowly added dropwise to a solution of 2.0 g (18 mmol) of N,N-diethyl-2-propynylamine (Example 1C1)) in 50 ml of tetrahydrofuran at -78° C. After one hour at -78° C., the mixture was warmed to room temperature, and 2.42 g (18 mmol) of 1-chloro-5-hexanone were added. Stirring at room temperature for one hour was followed by adjustment to pH 7 with 2 N hydrochloric acid and partitioning between 5% strength sodium bicarbonate solution and dichloromethane. The organic phase was dried over magnesium sulfate, the solvent was removed under reduced pressure. Yield: 4.38 (99% of theory); oily product
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][O:7][CH:8]2[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH:34]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[C:12]([C:13]#[N:14])=[CH:11][CH:10]=3)[CH2:5][CH2:6][O:7]2)[CH2:17][CH2:18]1
Reactant: COc1c(C#N)ccc2c1CCOC2CN1CCNCC1
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C#N)ccc2c1CCOC2CN1CCN(CCc2ccc3c(c2C)COC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(methyloxy)-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile (0.04 mmol) in 5 mL of DCM was added (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (from Step B, Intermediate 17, 11 mg, 0.06 mmol) and NaBH(OAc)3 (34 mg, 0.16 mmol), the mixture was stirred at room temperature overnight. The reaction was diluted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 1-({4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-5-(methyloxy)-3,4-dihydro-1H-isochromene-6-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[C@H:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29]C(OCC1C=CC=CC=1)=O)=[N:18]C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:40]>[Pd].CO.C(OCC)(=O)C>[ClH:40].[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([C:9](=[O:11])[CH3:10])[C:7](=[O:12])[C@H:6]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:29])=[NH:18])=[O:4]
Reactant: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 84 %

Procedure:
A methanol/ethyl acetate (2.5 mL/2.5mL) solution of compound 9 (313 mg, 0.58 mmol) and 1N HCl (0.58 mL) was stirred under a hydrogen atmosphere with 10% palladium on carbon catalyst. When the starting material had disappeared as determined by TLC, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated to afford 150 mg (84%) of the title product as a yellow foam.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:39])[CH2:33][CH2:34][O:35][CH:36]([CH3:38])[CH3:37]>>[CH3:37][CH:36]([O:35][CH2:34][CH2:33][C:32]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:28][N:31]=1)[CH3:38]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: CC(C)OCCC(N)=NO
Product: CC(C)OCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.24 mmol) of the compound from Example 100A and 60 mg (0.37 mmol) of the compound from Example 65A were reacted according to the General Method 2. Yield: 54 mg (42% of theory)
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[C:16](=[O:15])[N:11]3[CH2:10][CH:9]2[CH2:14][CH2:13][CH2:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CNC2CCCNC2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1N2CCCC(C2)N1Cc1ccccc1
Temperature: 0 °C
Yield: 30 %

Procedure:
1.06 g of the product obtained in stage C is dissolved in 28 cm3 of toluene, then cooled down to 0° C. and 337 μl of diphosgene is added under an inert gas. Then the temperature is left to rise and maintained for 2 hours at 20° C. The reaction medium is concentrated under reduced pressure then the residue is chromatographed on silica eluting successively with methylene chloride-acetone 95/5 then 80/20 and finally methylene chloride-methanol, triethylamine 92/8/3 and 362 mg of expected product C13H16N2O (M=216.85 g) is obtained i.e. a yield of 30%.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:37]=[CH:36][C:29]([O:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:37]=[CH:36][C:29]([O:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: CC(C)(CO)Oc1ccc(Br)cc1
Product: CC(C)(CO)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 2-(4-bromophenoxy)-2-methylpropan-1-ol.
Reaction SMILES: [CH3:1][C:2]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](O)=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3].C1([N:33]=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([NH2:33])=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3]
Reactant: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)CC(Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Analogously to the procedure described by Wang et al. in Synthesis 1989, 37 a mixture of 15.34 g (40mmol) of (S)-α-[[[(1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamic acid, 9.29 g (40 mmol) of dicyclohexylcarbodiimide and 6.89 g (50 mmol) of HOBT in 160 ml of methylene chloride and 40 ml of dimethylformamide was stirred at room temperature for 4 hours. Thereafter, the reaction mixture was filtered, the yellowish solution obtained was diluted with 200 ml of methylene chloride and cooled to 0°. Ammonia was conducted into this solution until it was saturated. The suspension obtained was stirred at room temperature for 1 hour. Subsequently, the solid formed was filtered off under suction and washed with 100 ml of methylene chloride. The yellow coloured filtrate was then washed twice with in each case 200 ml of water and twice with 200 ml of saturated sodium chloride solution. The wash solutions were extracted with 500 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and thereafter evaporated under reduced pressure. For purification, the yellowish crude product obtained (15.3 g) was chromatographed on 1.3 kg of silica gel using a 4:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 13.6 g of (S)-α-[[[(1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamamide as a colourless powder, MS: 383 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59])=[C:51]([OH:61])[CH:50]=1>>[C:58]([NH:57][CH2:56][CH2:55][C:52]1[CH:53]=[CH:54][C:49]([F:48])=[CH:50][C:51]=1[O:61][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: CC(=O)NCCc1ccc(F)cc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cc(F)ccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.27 g of N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.63 (EtOAc); Rt=5.61.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](=[N:17][OH:18])[NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=NO)C1CN(Cc2ccccc2)CCO1

Procedure:
Reaction of 4-benzylmorpholine-2-carbonitrile with hydroxylamine hydrochloride and sodium hydroxide provided 4-benzyl-N′-hydroxymorpholine-2-carboximidamide, which was condensed with cyclopropanecarboxylic acid using 1,3-dicyclohexylcarbodiimide. Cyclization using tetrabutylammonium fluoride (see A. R. Gangloff et al., Tetrahedron Lett. 2001, 42, 1441-1443), followed by debenzylation, afforded 2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)morpholine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:10]([O:12][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(Nc2cccc(F)c2)C(=O)O)cn1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2cccc(F)c2)C(=O)O[C@H]2CN3CCC2CC3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-fluorophenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I76) (48 mg, 0.17 mmol), (R)-quinuclidin-3-ol (24.31 mg, 0.19 mmol), HOBT (29.3 mg, 0.19 mmol), and DCC (39.4 mg, 0.19 mmol) was dissolved in THF (10 ml) and stirred at room temperature overnight. The solvent was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain the title compound, which was used in the next step without any further purification.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC.CCCCCCC>[CH2:23]([C:24]1[CH:23]=[C:23]([C:24]([CH:8]2[C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)([C:5]2[CH:17]=[CH:16][CH:15]=[CH:7][CH:6]=2)[C:25]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:26]=2)[CH2:26][CH:25]=1)[CH2:24][CH2:25][CH3:26]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Solvent: CCCCCCC
Solvent: CCOCC
Product: CCCCC1=CCC(C(c2ccccc2)(c2ccccc2)C2c3cc(C(C)(C)C)ccc3-c3ccc(C(C)(C)C)cc32)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 171.2 %

Procedure:
To 2,7-di-tert-butylfluorene (15 g, 54 mmol) dissolved in Et2O (100 mL) was added n-BuLi (5.8 mL of 10 M in hexanes, 58 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The anion solution was added to 2-butyl-6,6-diphenylpentafulvene (F-1) (16 g, 56 mmol) dissolved in Et2O (100 mL) at −78° C. in 5 minutes. The mixture was warmed to room temperature and stirred for 2 days. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with Et2O. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave a viscous oil. The oil was stirred in heptane to give a white solid. The solid was filtered, washed with heptane and dried under vacuum. A mixture of isomers for the desired product (18.7 g, 61.3% yield) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:41])[C:5]2[N:6]=[CH:7][N:8]([C:39]=2[N:40]=1)[C@@H:9]1[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:19]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@H:10]1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH:42]1([CH2:48][CH2:49][OH:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH:42]1([CH2:48][CH2:49][O:50][C:2]2[N:3]=[C:4]([NH2:41])[C:5]3[N:6]=[CH:7][N:8]([C:39]=3[N:40]=2)[C@@H:9]2[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:19]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@H:10]2[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: OCCC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCC4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C

Procedure:
To a dry 250-mL, 3-neck roundbottom flask was added 2-chloro-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)adenosine (5 g, 7.8 mmol, Example 1) and 2-(cyclohexyl)ethanol (15 mL). The mixture was flushed with nitrogen for 5–10 minutes, then heated to 50° C. To this mixture was added sodium hydride (1.56 g, 39 mmol, as a 60% dispersion in mineral oil) at such a rate as to avoid excessive gas evolution. The reaction was maintained at 50° C. until the reaction was complete by HPLC. The reaction was then cooled to room temperature, carefully quenched with water (50 mL), and extracted with ethyl acetate (100 mL, 2×60 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford a viscous oil. This material was purified by passing through a plug of silica gel, eluting with CH2Cl2, 2% MeOH in CH2Cl2, 5% MeOH in CH2Cl2, and 10% MeOH in CH2Cl2. Those fractions containing products were combined and evaporated to dryness, to afford a mixture of monosilyl-protected and disilyl-protected alkylated products (LC/MS m/z=622 and 508). This mixture was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29]>CN(C)C=O>[F:26][C:27]([F:33])([F:32])[S:28]([O:19][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:13])[CH2:6]2)(=[O:30])=[O:29]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A mixture of (+)-6,7dichloro-2-cyclopentyl- -2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (25.05 g, 0.0837 mole) and potassium carbonate (35.4 g. o.256 mole) in dimethylformamide (100 ml.) is stirred at 25° C. for 1 hour, cooled to 0° C. then treated with trifluoromethanesulfonyl chloride (10.5 ml., 0.984 mole) over a 3 minute period. The reaction mixture is stirred at 25° C. for 1 hour, poured into ice water (700 ml.) extracted with ether, washed with water and brine and dried over MgSO4. The ether is evaporated at reduced pressure to give 34.2 g of (+) (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H- -inden-5-yl) trifluoromethanesulfonate which melts at 104°-6° C. and is used in Step B without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.1 %

Procedure:
To a pre-stirred solution of 4-bromo-2-fluorobenzaldehyde (1.82 g, 9.0 mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at 0° C. was added sodium triacetoxyborohydride (2.85 g, 13.4 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and stirred for an additional 14 h. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.6 g, 84%) that was used in the next step without further purification. NMR (CDCl3, 400 MHz): 7.33-7.17 (m, 3H), 3.49 (d, J=1.6 Hz, 2H), 2.43-2.33 (m, 4H), 1.61-1.53 (m, 4H), 1.46-1.38 (m, 2H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>CS(C)=O>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:4]2[C:5](=[O:17])[C:6](=[O:16])[C:7]=2[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[C:21]([CH3:26])[CH:20]=1
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Cc1cc(Br)ccc1N
Solvent: CS(C)=O
Product: Cc1cc(Br)ccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 4-bromo-2-methylaniline (40 mg, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 373 (M+).