Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].[CH:12]1([O:17][C:18]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[N:21][NH:22][CH:23]3Cl)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C)C=O>[CH:12]1([O:17][C:18]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[N:21][N:22]=[C:23]3[CH2:8][C:7]2[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(c1OC1CCCC1)C=NNC2Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OC1CCCC1
Reaction time: 1 h
Yield: 57.1 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (13.86 g, 85.56 mmoles) in dry dimethylformamide (100 ml) was added, under nitrogen and stirring, with 55% NaH (3.73 g, 85.56 mmoles). The mixture was stirred for 1 hour then added with a solution of 5-cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine (7.95 g, 28.52 mmoles), obtained as described in example 7, in dry dimethylfomamide (70 ml). The mixture was left to stand for one night, quenched with water, diluted with water and extracted methyl aceate. The extract was washed with water and anhydrified over Na2SO4, then evaporated to dryness. The residue was flash chromatographed (eluent:petrolatum/ethyl acetate 1:1) to give 6.58 g of the title product (yield: 57%).
Reaction SMILES: Cl[C:2]1[C:7](CCC(O)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)CCc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccccn2)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
Pd(PPh3)4 (3.0 g, 2.6 mmol) was added to a solution of 2-chloro-3-carboxyethylpyridine (25 g, 134.7 mmol), phenylboronic acid (21.04 g, 172.6 mmol) and K2CO3 (55.1 g, 399 mmol) in 1,4-dioxane (200 mL) and water (200 mL). The reaction mixture was heated at 100° C. for 2 h. The solution was then cooled to room temperature and the dioxane was removed under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (Na2SO4), filtered through celite, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10-100% EtOAc/hexanes) to get the 2-phenylpyridine derivative in 91% yield (27.98 g). LC-MS Rt (retention time): 2.45 min, MS: (ES) m/z 228 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])C.C1N=CN([C:17]([N:19]2C=NC=C2)=[O:18])C=1.Cl.[CH2:25]([O:28]N)[CH:26]=[CH2:27].CCN(CC)CC>C1(C)C=CC=CC=1>[CH2:25]([O:28][N:19]1[C:4](=[O:5])[C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH:11][C:17]1=[O:18])[CH:26]=[CH2:27]
Reactant: C=CCON
Reactant: CCOC(=O)c1sccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOn1c(=O)[nH]c2ccsc2c1=O
Yield: 45.6 %

Procedure:
3-Amino-thiophene-2-carboxylic acid ethyl ester (2 grams, 12.7 mmol) and CDI (2.3 g, 14 mmol) were refluxed 20 mL in toluene overnight. O-Allyl hydroxylamine hydrochloride (1.7 g, 15.5 mmol) and Et3N (2.2 mL, 15.5 mmol) were added and solution was again brought to reflux for 3 hours. The solution was cooled, concentrated, and redissolved in 25 mL hot ethanol. NaOH was added (16 mL of a 2 M aq. solution) and the mixture was heated to reflux for 1 hour. The reaction mixture was acidified with 1 mL of glacial acetic acid and cooled. The resultant precipitate was filtered and discarded. The filtrate was concentrated, treated with 20 mL of ethanol, sonicated briefly, and then filtered to give 1.3 grams of 3-allyloxy-1H-thieno[3,2-d]pyrimidine-2,4-dione.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]([OH:13])=[CH:11][C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=1.[H][H].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O>[CH3:17][O:18][CH2:19][O:13][C:12]1[C:4]([Br:3])=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: [H][H]
Reactant: COCCl
Reactant: Oc1cc2c(cc1Br)OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc2c(cc1Br)OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flame-dried 1000 mL 3-neck flask fitted with an internal thermometer, magnetic stirring, and a 250 mL dropping funnel was charged with sodium hydride (60% dispersion in mineral oil, 11.17 g, 279 mmol) and dimethylformamide (dried over molecular sieves, 200 mL). A solution of 16 (50.00 g, 233 mmol) in dimethylformamide (100 mL) was added dropwise such that the reaction temperature did not exceed 40° C (addition time was approximately 30 minutes). When hydrogen evolution had ceased, an ice bath was added and chloromethyl methylether (22.47 g, 297 mmol) was added dropwise at 25° C. Upon completion of the addition the reaction mixture was allowed to stir at room temperature for two hours then quenched by pouring into water (1000 mL). The mixture was extracted with ether (3×300 mL) and the combined organic extracts washed sequentially with water (2×500 mL) and 20% NaCl (300 mL), dried (Na2SO4), and concentrated. Distillation afforded 17 as a colorless liquid.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3([C:20]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27]([C:32]([CH3:43])([CH3:42])[CH2:33][NH:34]C(=O)OC(C)(C)C)=[CH:26]5)=[O:21])[CH2:19][CH2:18]3)=[CH:16][C:11]=2[O:10][CH2:9]1>ClCCl>[NH2:34][CH2:33][C:32]([C:27]1[NH:28][C:29]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH:22][C:20]([C:17]1([C:15]3[CH:14]=[CH:13][C:12]4[O:8][CH2:9][O:10][C:11]=4[CH:16]=3)[CH2:19][CH2:18]1)=[O:21])=[CH:31][CH:30]=2)([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
Trifluoroacetic acid (0.75 mL) was added to a solution of tert-butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-2-methylpropylcarbamate (77 mg, 0.16 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness to give N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (53 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.18-7.15 (m, 2H), 7.02-6.94 (m, 3H), 6.85 (d, J=7.8 Hz, 1H), 6.14 (d, J=1.2 Hz, 1H), 6.02 (s, 2H), 2.84 (s, 2H), 1.68 (dd, J=3.6, 6.7 Hz, 2H), 1.32 (s, 6H), 1.08 (dd, J=3.7, 6.8 Hz, 2H).
Reaction SMILES: [C:1]1([S:10]([NH:13][C:14](=[O:17])[CH2:15][NH2:16])(=[O:12])=[O:11])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].Cl[C:21]([O:23][CH3:24])=[O:22].O>CN(C)C=O>[C:1]1([S:10]([NH:13][C:14](=[O:17])[CH2:15][NH:16][C:21]([O:23][CH3:24])=[O:22])(=[O:11])=[O:12])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)Cl
Reactant: NCC(=O)NS(=O)(=O)c1scc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)NCC(=O)NS(=O)(=O)c1scc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product obtained in Step 1 (0.45 g) in N,N-dimethylformamide (5 ml) was added slowly 60% sodium hydride (75 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Methyl chloroformate (0.14 ml) was added to the above-mentioned mixture followed by stirring for 20 minutes at room temperature. 60% sodium hydride (75 mg) was added to the solution, and the mixture was stirred for 1.5 hours at room temperature, then 15 minutes at 70° C. After cooling to room temperature, water (20 ml) was added to the resultant mixture and this aqueous solution was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water, then saturated aqueous NaCl solution. After drying over anhydrous magnesium sulfate, ethyl acetate was removed in vacuo and the residue was purified by silica-gel columun chromatography to give 0.18 g of the objective compound.
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH2:36]Br)[CH:33]=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39])[CH2:36][CH:8]([CH2:9][CH3:10])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenylbutan-1-one (203 mg, 1.37 mmol) in THF (2.5 mL) at −78° C. is added dropwise LiHMDS (1.62 mL of 1.0 M solution in THF, 1.62 mmol) over a period of 15 min. The solution is stirred at −78° C. for 1 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (400 mg, 1.25 mmol) in THF (2.5 mL) is added dropwise. The mixture is allowed to warm to RT and stirred there for 1 h then is quenched with saturated ammonium chloride solution. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 5-100% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:35][CH:34]=1>C1COCC1>[Si:41]([O:40][CH2:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])=[CH:38][CH:37]=1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43]
Reactant: N#CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CC(C#N)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of phenylacetonitrile (1.5 mL, 12.7 mmol) in THF (40 mL) containing HMPA (11 mL, 63.4 mmol) was cooled to -78° C. and treated with 16 mL (16 mmol) of a 1.0M THF solution of lithium bis(trimethylsilyl)amide dropwise while the temperature was maintained at -78° C. The reaction was stirred at -78° C. for 1.5 hours, and a solution of the product of Step B (2.00 g, 6.34 mmol) in THF (8 mL) was added dropwise with the temperature maintained below -70° C. The reaction temperature was maintained below -68° C. for 3 hours. The reaction was quenched at this temperature by addition of 1N Na2HSO4. After warming to room temperature, the mixture was partitioned between EtOAc and water, and the combined organic layers were washed with water, saturated NaHCO3, brine, dried (MgSO4), filtered, then concentrated in vacuo. The residue was chromatographed on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.5 g (67%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:22])[CH2:18][N:19]=[N+]=[N-])[CH:13]=2)[NH:8][C:7]=1[CH3:23])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:22])[CH2:18][NH2:19])[CH:13]=2)[NH:8][C:7]=1[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN=[N+]=[N-])cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN)cc12
Reaction time: 4 h
Yield: 101.1 %

Procedure:
A solution of 0.56 g (1.76 mmol) of 5-((2S)-3-azido-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (which was obtained in Example 140) and 1.2 g of triphenylphosphine polymer resin (3 mmol/g) was stirred in 15 mL toluene for 1.5 hours under nitrogen. The resin was collected by filtration and washed twice with 25 mL of toluene. The resin was then stirred in 60 mL of 9:1 THF/methanol for four hours. The resin was removed by vacuum filtration and washed with 9:1 THF/methanol. The filtrate was concentrated in vacuo. Then the solid was dried under vacuum to give 0.52 g of the title compound as a beige solid; mp 66–68° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.32–1.37 (m, 3H), 1.80 (brs, 1H), 2.61 (s, 3H), 2.69–2.75 (m, 2H), 3.69–3.76 (m, 1H), 3.82–3.95 (m, 2H), 4.23 (q, J=6.93 Hz, 2H), 4.90 (brs, 1H), 6.76 (dd, J=2.52 Hz, 8.73 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 8.85 (brs, 1H), 11.65 (s, 1H); MS (ES) m/z: 293.0 (MH+); HRMS Calcd. for C15H21N2O4(MH+): 293.1501. Found: 293.1498.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:18])([C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH2:11])[C:3]([OH:5])=[O:4]
Reactant: C=C(c1ccccc1)C(C)(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(c1ccccc1)C(C)(C)C(=O)O

Procedure:
tert-Butyl 2,2-dimethyl-3-phenylbut-3-enoate and trifluoroacetic acid were reacted in methylene chloride at room temperature to obtain 2,2-dimethyl-3-phenylbut-3-enoic acid.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].[CH3:14][S-:15].[Na+]>>[CH3:8][N:7]1[C:2]([S:15][CH3:14])=[C:3]([CH:12]=[O:13])[C:4](=[O:11])[N:5]([CH3:10])[C:6]1=[O:9]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: C[S-]
Agent: [Na+]
Product: CSc1c(C=O)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method D was followed. 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.404 g, 2.00 mmol) and sodium thiomethoxide (0.154 g, 2.20 mmol in 4 ml 1,4-dioxane) were used to obtain the title compound. The crude product was purified by washing with n-pentane.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH:2]=[CH2:3].[CH2:24]([O:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH2:25][CH2:26][CH3:27].[C:33]([O:37]CCO)(=[O:36])[CH:34]=[CH2:35].CC(N=NC(C#N)(C)C)(C#N)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH:2]=[CH2:3].[C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:32])[CH:30]=[CH2:31].[OH:4][C:34](=[CH2:35])[C:33]([O-:37])=[O:36]
Reactant: C=CC(=O)OCCO
Agent: C=CC(=O)OCCCC
Agent: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(O)C(=O)[O-]

Procedure:
To a 1 L flask equipped with a stirrer, a nitrogen introducing tube, a thermometer and a condenser, 50 g of stearyl acrylate, 49 g of n-butylacrylate, 1 g of hydroxyethyl acrylate, 0.89 g of AIBN, 100 mL of toluene and 100 mL of ethyl acetate were added and subjected to polymerization reaction in a stream of nitrogen at 70° C. for 12 hr, to obtain a copolymer of stearyl acrylate, n-butyl acrylate and hydroxyacrylate (hereinafter sometimes referred to “PSABAHEA”. The resulting PSABAHEA had a weight average molecular weight of 170,000.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4ccc5[nH]ccc5c4)CC3)noc2c1
Yield: 123.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8 mmol), K2CO3 (1.6 g, 11.6 mmol), KI (200 mg), 5-(3-chloropropoxy)indole (2.2 g, 10.5 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed 2 times with H2O, 2 times with brine and after drying with MgSO4 the solvent was removed in vacuo to yield 5.1 g of a dark oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500, using 2 silica gel columns and 4% MeOH-CH2Cl2 as eluent) to afford 2.65 g (65%) of a beige solid. Recrystallization from ethanol gave 2.2 g (54%) of a beige powder, m.p.=118°-121° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S-:17][C:18]#[N:19].[NH4+].[NH2:21][C:22]1[C:23](Cl)=[N:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>CC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:14])[NH:19][C:18]2[S:17][C:23]3[C:22]([N:21]=2)=[C:27]([O:28][CH3:29])[CH:26]=[CH:25][N:24]=3)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccnc(Cl)c1N
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)Cl)C1
Agent: [NH4+]
Solvent: CC(C)=O
Product: COc1ccnc2sc(NC(=O)N3CCC(NC(=O)OC(C)(C)C)C3)nc12
Yield: 14.6 %

Procedure:
A magnetically stirred mixture of (1-Chlorocarbonyl-pyrrolidin-3-yl)carbamic acid tert-butyl ester (820 mg, 3.30 mmol) in acetone (15 mL) under a nitrogen atmosphere at 25 C was treated with ammonium thiocyanate (240 mg, 3.15 mmol). The reaction mixture was stirred at reflux for 30 min. At this time, the reaction was treated with 3-amino-2-chloro-4 methoxypyridine (440 mg, 2.78 mmol). The reaction mixture was refluxed overnight. At this time, the reaction was concentrated in vacuo, poured into water and extracted with ethyl acetate. The organics were washed with a 2N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98:2 methylene chloride/methanol) afforded [1-(7-Methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (160 mg, 15%) as a light yellow solid. LRMS for C17H23N5O4S (M+H)+ at m/z=393. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)O1.I[C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:39][C:38]1[C:20]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:21][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2)OC1(C)C
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
4,4,5,5-Tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborolane (1.4 g, 5.6 mmol) was mixed with 3-iodo-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide (2.00 g, 4.94 mmol), potassium carbonate (1.4 g, 9.9 mmol), toluene (40 mL), ethanol (6.0 mL), and water (4.0 mL). The mixture was degassed and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.24 mmol) was added. The resulting mixture was heated to reflux for 16 hours. The reaction was then cooled and was extracted with ethyl acetate. The organic extracts were washed with water, brine, dried (Na2SO4) and concentrated. The product was purified by flash column chromatography, eluting with a gradient of 20-50% ethyl acetate in hexanes (1.92 g, 91%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[NH2:23][C@H:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:23][C@H:24]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]2)=[N:3]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1ccc(F)cc1
Reactant: N[C@@H]1CCc2ccccc21
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1

Procedure:
N-(2-Chloro-quinolin-5-yl)-4-fluoro-benzenesulfonamide (300 mg, 0.891 mmol) and (R)-1-aminoindane (254 mg, 1.91 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a yellow solid (287 mg, 74%), MS:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A solution of 2-bromo-1-(2,4-difluorophenyl)ethanone (5.0 g, 21.3 mmol) and potassium thiocyanate (2.07 g, 21.3 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture. A crystal was collected by filtration and washed with 50% aqueous ethanol to give 3.39 g (74.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]/[CH:7]=[CH:8]/[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2].[Cl-].[Li+].[Li+].CC([N-]C(C)C)C.[CH3:25][O:26][CH2:27][CH2:28]Br.C1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([CH2:31][CH2:32][O:33][CH3:34])[CH:8]=[CH:7][CH:6]([CH2:28][CH2:27][O:26][CH3:25])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:14]
Reactant: C1CCOC1
Reactant: COCCBr
Reactant: CCOC(=O)C/C=C/CC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Product: CCOC(=O)C(C=CC(CCOC)C(=O)OCC)CCOC
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 16 %

Procedure:
To a stirred solution of 5.0 g (25.0 mmol) trans-2-butene-1,4-dicarboxylic acid diethyl ester in 125 ml THF was added 6.35 g (150 mmol) anhydrous lithium chloride and the resulting suspension cooled to −78° C. 25.0 ml (50.0 mmol) of a 2 M solution of LDA in THF was added dropwise and stirring continued for 45 min. 7.4 ml (78.7 mmol) 2-methoxyethyl bromide was then added and stirring continued for 15 min at −78° C., then 1 h at 0° C., and then 2 h at room temperature. The reaction was quenched by addition of saturated ammonium chloride solution and the mixture extracted three times with ether. The combined organic phases were washed successively with saturated ammonium chloride solution, water, and saturated brine, dried over sodium sulphate, and concentrated in vacuo. Flash chromatography (50% toluene in EtOAc) afforded 1.29 g (16%) of the title compound as a yellow oil. MS m/e (%): 334 ([M+NH4]+, 100).