Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:10][C@@H:9]2[C@@H:5]([O:6][C:7]([CH3:12])([CH3:11])[O:8]2)[C@@H:4]1[OH:13].C([O-])(O)=[O:15].[Na+].[Na+].[Br-].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.O.CC1(C)N([O])C(C)(C)CCC1.CO>[OH:13][C@H:4]1[C@@H:5]2[O:6][C:7]([CH3:11])([CH3:12])[O:8][C@@H:9]2[O:10][C@H:3]1[C:2]([OH:15])=[O:1]
Reactant: O=C([O-])O
Reactant: CC1(C)O[C@@H]2O[C@@H](CO)[C@@H](O)[C@@H]2O1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Temperature: 0 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a solution of (3aS,5S,6R,6aS)-5-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol (14.6 g, 76.7 mmol), NaHCO3 (19.3 g, 230.3 mmol) and NaBr (1.6 g, 15.4 mmol) in acetone/water (120/40 mL) was added TEMPO (2,2,6,6-Tetramethyl-1-piperidinyloxy free radical) (0.24 g, 1.5 mmol) at room temperature. The mixture was cooled to 0° C., and trichloroisocyanuric acid (17.8 g, 76.7 mmol) was then added in portions. The suspension was stirred for 12 h at room temperature. Methanol (2.0 mL) was added and the mixture was stirred for 2 h at room temperature. The mixture was filtered, washed with acetone (twice, 20 mL per wash). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc and the organic layer was concentrated in vacuo. Acetone was added and the mixture was filtered. The filtrate was concentrated to afford the desired acid (9.0 g, 58%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1>>[O:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:2]#[C:1][C:3]3[CH:15]=[CH:14][C:6]4[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=4[CH:4]=3)=[CH:18][C:19]=2[O:23][CH2:22]1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: Ic1ccc2c(c1)OCO2
Product: CC1(C)COc2ccc(C#Cc3ccc4c(c3)OCO4)cc2OC1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 5-iodo-benzo[1,3]dioxole. MS (ESI) 322.2 (M•)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:17][CH:18]=2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: ClCCCOc1c(Cl)cc(-c2csc(-c3ccccc3)n2)cc1Cl
Product: Clc1cc(-c2csc(-c3ccccc3)n2)cc(Cl)c1OCCCn1ccnc1

Procedure:
The title compound was prepared as described in Example 22 using 4-[3,5-dichloro-4-(chloropropoxy)phenyl]-2-phenylthiazole (4.2 g, 11 mmol) and imidazole (2.2 g, 33 mmol) in place of dibutylamine to give 1.9 g (40% yield) of the free base of the title compound which was converted to the HCl salt, mp 204°-207° C. IR(KBr): 3400, 2540 cm-1, MS: 430(MH+). 1H NMR (CD3OD): δ9.08 (brs, 1H), 8.03-7.48 (m, 10H), 4.65 (t, J=5.0 Hz, 2H), 4.12 (t, J=4.5 Hz, 2H), 2.50 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH3:54][O:55][C:56](=[O:61])[C@H:57]([CH2:59][OH:60])[NH2:58]>CN(C=O)C.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:58][C@H:57]([C:56]([O:55][CH3:54])=[O:61])[CH2:59][OH:60])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
500 mg (1.57 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 6A, 756 mg (2.36 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 794 mg (7.89 mmol) of 4-methylmorpholine were initially charged in 3 ml of DMF. After 10 min at RT, 293 mg (1.89 mmol) of (5)-serine methyl ester hydrochloride were added and the mixture was stirred at RT overnight. About 80 ml of water were added to the reaction solution, and the precipitate formed was stirred for another 30 min, filtered off, washed thoroughly with cold diethyl ether and dried under high vacuum overnight. This gave 601 mg of the target compound (89% of theory, purity 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][C:12]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][C:12]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(O)c2ccccc2)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
A mixture of [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl]phenyl)phenylmethanol (reference example 6-1) (526 mg), manganese dioxide (1.18 g) and methylene chloride (6.8 mL) was stirred at room temperature overnight. After addition of manganese dioxide (1.18 g), the mixture was stirred for 7.5 hours, and manganese dioxide (0.59 g) was added, and the mixture was stirred overnight. The mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure to give the title compound (526 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][C:37]([CH3:41])([OH:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][C:37]([CH3:41])([OH:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC1(O)CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(C)(O)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.207 g, 0.53 mmol), 1-azetidin-3-yl-4-methylpiperidin-4-ol (0.108 g, 0.63 mmol) and 4 Å molecular sieves (0.5 g) in DCE (5 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.224 g, 1.06 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 30:70) to give 551 as a white solid (0.247 g, 86%). LCMS (Method I): RT=2.35 min, [M+H]+ 546.3. 1H NMR (400 MHz, DMSO-d): δ 8.04-7.98 (m, 1 H); 7.65-7.60 (m, 1 H); 7.27-7.20 (m, 2 H); 4.34-3.83 (m, 4 H); 3.85 (s, 2 H); 3.79-3.75 (m, 7 H); 3.43 (t, J=7.4 Hz, 2 H); 3.31-3.20 (q, J=7.4 Hz, 2 H); 2.96-2.93 (m, 2 H); 2.92-2.83 (m, 1 H); 2.27-2.23 (m, 2 H); 2.18-2.14 (m, 2 H); 1.48-1.36 (m, 4 H); 1.33 (t, J=7.4 Hz, 3 H); 1.12-1.06 (s, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (190 mg, 79%). MS (ISN) 477.0 [(M−H)−]; mp 216° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:62][CH2:61][CH:60]([O:63][CH2:64][C:65](O)=[O:66])[CH2:59][CH2:58]2)=[CH:52][C:51]=1[C:68]([F:71])([F:70])[F:69])([O-:49])=[O:48]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:65](=[O:66])[CH2:64][O:63][CH:60]4[CH2:61][CH2:62][CH:57]([NH:56][C:53]5[CH:54]=[CH:55][C:50]([N+:47]([O-:49])=[O:48])=[C:51]([C:68]([F:70])([F:69])[F:71])[CH:52]=5)[CH2:58][CH2:59]4)[CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:17]=1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Fc1ccc2sc(CN3CCNCC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2nc3cc(F)ccc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A mixture of 5-fluoro-2-(piperazin-1-ylmethyl)-1,3-benzothiazole (130 mg, 0.52 mmol), EDAC.HCl (149 mg, 0.78 mmol), HOBt (105 mg, 0.78 mmol) and triethylamine (157 mg, 1.55 mmol) in dichloromethane (30 ml) was stirred for 1 hour at room temperature before the addition of 2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acid (187 mg, 0.52 mmol). After stirring overnight at room temperature, the solution was diluted with dichloromethane (100 ml) and washed with water (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by HPLC to afford 1-(4-((5-fluorobenzo[d]thiazol-2-yl)methyl)piperazin-1-yl)-2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanone as a yellow solid (162.0 mg, 53%). (ES, m/z): [M+H]+ 596.00; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=9.0 Hz, 1H), 7.87 (dd, J=8.7, 4.8 Hz, 1H), 7.72 (dd, J=9.0, 2.4 Hz, 1H), 7.29-7.23 (m, 1H), 6.84 (d, J=2.1 Hz, 1H), 6.62 (dd, J=9.0, 2.1 Hz, 1H), 5.52 (br s, 1H), 4.47 (s, 2H), 4.20 (s, 2H), 3.93-3.90 (m, 4H), 3.43-3.33 (m, 2H), 3.22-3.19 (m, 4H), 2.11-2.01 (m, 4H), 1.48-1.37 (m, 2H), 1.32-1.21 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>C1C=CC=CC=1>[CH3:3][C:2]1[CH2:1][CH:8]2[C:7](=[O:13])[O:12][C:10](=[O:11])[CH:9]2[CH2:5][C:4]=1[CH3:6]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CC1=C(C)CC2C(=O)OC(=O)C2C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84.9 %

Procedure:
A mixture of 2,3-dimethyl-1,3-butadiene (10 g; 0.122 mol), maleic anhydride (11.9 g; 0.122 mol) and benzene (30 ml) was stirred at room temperature for 10 hours, followed by removal of insoluble materials by filtration. The filtrate was concentrated under reduced pressure to give the objective compound (18.66 g). Yield, 86.6%. M.P., 73°-74° C.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([C:19]2[NH:18][C:15]3=[N:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)[CH:13]=[C:14]3[CH:20]=2)=[O:23])=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Reactant: NCc1ccc(F)cc1
Agent: Cl
Product: O=C(NCc1ccc(F)cc1)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Yield: 55 %

Procedure:
The title compound was synthesized in analogy to example 1 from 5-(3-piperidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride and 4-fluorobenzylamine to give the desired product as light brown solid (55%).
Reaction SMILES: C([O:4][C:5]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[C:11]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[S:8])(=O)C.C1COCC1.CO.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:11]2[C:10]([NH:9][C:7](=[S:8])[C:6]3[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:5]=3[OH:4])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:17])=[N:20][CH:21]=1
Reactant: CC(=O)Oc1cc(C)ccc1C(=S)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a mixture of 3-[2-acetoxy-4-methylthiobenzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (13 g, 28.4 mmol), THF (100 mL) and MeOH (50 mL) was added Na2CO3 (5.75 g, 54.3 mmol), and the mixture was stirred for 18 h. The resulting yellow suspension was diluted with dichloro-methane (100 mL), and 1 N HCl (about 55 mL) was slowly added. The mixture was partitioned and the white organic suspension was concentrated. The residue was triturated with dichloromethane (200 mL) and filtered to give the title compound as a white solid (9.5 g, 22.9 mmol, 80%).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[OH-].[Na+].CO.C(=S)=[S:26]>>[CH:11]1[N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:19]2[C:13](=[C:14]([NH2:15])[NH:16][C:17]([N:18]=2)=[S:26])[N:12]=1
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 92 %

Procedure:
8.0 g of adenosine 1-oxide (26.67 mmol) was refluxed in 75 ml of a 5N sodium hydroxide aqueous solution for 15 minutes. The resulting liquid was neutralized to a pH of 5.0 with Amberlite IRC-50 (H+-type) and concentrated to a small volume to prepare 1-β-D-ribofuranosyl-5-aminoimidazole-4-carboxamide oxime. To this was added 200 ml of an aqueous solution containing 175 ml of methanol, the resulting solution being found to have a pH of 9. 50 ml of carbon disulfide was added to the solution, and the mixture was allowed to react in an autoclave at 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2). The orange colored substance formed was removed and concentrated to dryness. The residue was dissolved in 63 ml of 2.5N aqueous ammonia, and any impurities were filtered out. A mixture of n-butanol and acetic acid (125 ml: 63 ml) was added to the filtrate to crystallize the product to obtain 5.42 g of 2-thioadenosine having a melting point of 199° C (with decomposition) in a 92% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:40]([N:47]1[CH2:51][CH2:50][C@H:49]([C:52](O)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:40]([N:47]1[CH2:51][CH2:50][C@H:49]([C:52]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)[C@H]1CCN(Cc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)[C@H]1CCN(Cc2ccccc2)C1
Yield: 21.8 %

Procedure:
This compound was prepared according to method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.181 g; 0.476 mmol), (S)-1-benzylpyrrolidine-3-carboxylic acid hydrochloride (0.119 g; 0.476 mmol), and N,N-diisopropylethylamine (0.189 mL; 1.08 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of a solution of 5% ammonium hydroxide in methanol, in dichloromethane) to afford 0.036 g (22%) of (S)-1-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[OH:14].[CH2:15]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26]Br)[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([O:9][C:6]1[CH:5]=[CH:4][C:3]([O:14][CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]2)=[C:2]([F:1])[C:7]=1[F:8])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC[C@H]1CC[C@H](CBr)CC1
Reactant: CCCCOc1ccc(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(OCCCC)c(F)c2F)CC1

Procedure:
0.1 mol of 2,3-difluoro-4-butoxyphenol, 0.11 mol of trans-4-pentylcyclohexylmethyl bromide and 0.11 mol of potassium carbonate are heated at 100° in 100 ml of dimethylformamide (DMF) for 16 hours. After cooling, the inorganic salts are filtered off with suction, the filtrate is concentrated and water is added. Extraction with methylene chloride gives 1-butoxy-2,3-difluoro-4-(trans-4-pentylcyclohexylmethoxy)benzene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:42][CH2:43][C@H:44]([CH:47]=[C:21]([Br:24])[Br:20])[CH2:45][CH2:46]1)[CH3:39])([CH3:35])([CH3:33])[CH3:34]
Reactant: BrC(Br)(Br)Br
Reactant: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C[C@H]1CC[C@H](C=C(Br)Br)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 257.6 g (982 mmol) triphenylphosphine in 1 l CH2Cl2 was treated with 162.8 g (491 mmol) tetrabromomethane (the reaction heated up to reflux and was then cooled with an ice bath) and after 40 min at RT with 157.4 ml (1129 mmol) triethylamine (the reaction heated up to reflux and became dark violet). After cooling (0° C.), 77.96 g (corresponds to 245.5 mmol) of crude trans-(4-Formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester in 600 ml CH2Cl2 were added during 20 min. The solution was stirred for 20 h at RT, evaporated and filtered through silica gel (deactivated with hexane/0.5% Et3N) with hexane/Et2O 99:1 to 4:1 as eluent to yield 61.5 g (61%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester, MS: 409 (M, 2Br).
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12].C([O-])(=O)C.[K+]>>[C:11]([O:10][CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC=O
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCCCCCC=COC(C)=O

Procedure:
A mixture of one mole of nonanal, 2.5 moles of acetic anhydride, and 15 g. of anhydrous potassium acetate is refluxed for one hour and cooled. Excess acid is removed by a 2X wash with water, followed by 5% sodium carbonate wash to give 1-nonen-1-yl acetate as a relatively pure oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14]C=N2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:16]1[CH:20]=NC=N1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:20]=[N:16][CH:14]=[N:15]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: c1nc[nH]n1
Product: Cc1ccc(-n2cncn2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 1H-1,2,4-triazole. ESI-MS (m/z): 204 [M+1]+.
Reaction SMILES: Br[C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:25][SH:26]>CN(C=O)C.CCOCC>[Br:18][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([S:26][CH3:25])[C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: CCOC(=O)c1ccc(Br)c(OCCOC)c1Br
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Br)c(OCCOC)c1SC

Procedure:
Ethyl 2,4-dibromo-3-(2-methoxyethoxy)benzoate(32.2 g) was stirred in DMF (80 ml) with potassium carbonate (36 g). To the resultant suspension was added a solution of methane thiol (13 ml) in DMF (20 ml). The resultant mixture was stirred overnight at room temperature. It was then diluted with ether, and the mixture washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography on silica eluting with ethyl acetate and cyclohexane (1:20) which yielded ethyl 4-bromo-3-(2-methoxyethoxy)-2-methylsulphenylbenzoate (3.5 g) as an oil which was not further characterized.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[C:25]=3[F:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cccc(F)c1F
Product: CCCNC(=O)c1nnc2c(-c3cccc(F)c3F)cccc2c1N
Yield: 55.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,3-difluorophenyl boronic acid (153 mg, 0.97 mmol) were reacted to afford the title compound (63 mg, 57.6% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.95 (dd, J=8.0 Hz, J′=1.7 Hz, 1H), 7.70-7.85 (m, 2H), 7.15-7.30 (m, overlapped with CHCl3), 3.46 (q, J=6.7 Hz, 2H), 1.66 (m, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=343 (M+H) HPLC 2.08 min.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=3)[C:5]3([CH2:21][O:20][CH2:19][C:18](=[O:22])[NH:17]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][CH2:19][C:18](=[O:22])[NH:17]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)CI
Reactant: O=C1COCC2(N1)c1cc(O)ccc1Oc1ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COCC(=O)N1)c1cc(Br)ccc1O2
Temperature: 115 °C

Procedure:
In a 25-ml flask, 2′-bromo-7′-hydroxyspiro[morpholine-3,9′-xanthen]-5-one (0.020 g, 0.055 mmol) was dissolved in DMF (1 mL). Cesium carbonate (0.043 g, 0.133 mmol) was added, followed by 1-iodo-2,2-dimethylpropane (0.022 g, 0.110 mmol). The reaction was heated in a 115° C. oil bath for 10 h. The reaction was cooled to ambient temperature and concentrated. The residue was taken up in 0.3 M aqueous HCl (15 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The organic layers were combined, washed with saturated brine (5 mL), dried over sodium sulfate, and concentrated. The residue was purified by chromatography (25% EtOAc/hexane) to afford (R)-2′-bromo-7′-(neopentyloxy)spiro[morpholine-3,9′-xanthen]-5-one.