Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1([CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.C1(C=CC(O)=CC=1)O>[C:22]1([S:28]([CH:31]2[CH2:32][C:10]3([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:9]([CH2:8][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:14]2[CH:13]=[CH:12][C:11]3=[O:15])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [Br-]
Solvent: CO
Product: O=C1C=CC2C(S(=O)(=O)c3ccccc3)CC1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To 7.35 gm (21.5 mmol) 1-phenylmethyl-2-phenyl-3-hydroxypyridinium bromide in 20 ml of methanol was added 8.69 gm Amberlyst AG1-X8 resin —OH form 20–40 mesh. The mixture was stirred for a short period and then filtered and the resin washed with methanol. The solvent was removed in vacuo. The solid residue was taken up in toluene (150 ml) and treated with 50 mg of hydroquinone and 6.84 gm (37.1 mmol) phenyl vinylsulfone. The reaction mixture was heated under reflux for 18 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 8:2/hexane:ethyl acetate to afford 5.87 gm (64%) of a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.71–7.61 (m, 5H), 7.46 (t, 2H, J=8 Hz), 7.37–7.23 (m, 8H), 6.84 (dd, 1H), J=9 Hz, J=5 Hz), 6.20 (d, 1H, J=9 Hz), 4.22 (d, 1H, J=5 Hz), 3.63 (d, 1H, J=14 Hz), 3.54 (dd, 1H, J=9 Hz, J=4 Hz), 3.40 (d, 1H, J=13 Hz), 2.80 (dd, 1H, J=15 Hz, J=3 Hz), 2.53 (dd, 1H, J=15 Hz, J=5 Hz) ppm. 13C NMR (CDCl3, 125 MHz) δ 196.9, 144.9, 138.3, 138.0, 137.7, 134.3, 130.9, 129.9, 129.8, 129.5, 129.2, 129.2, 129.0, 129.0, 128.9, 128.7, 128.2, 128.1, 127.9, 75.1, 66.3, 57.9, 49.1, 38.1 ppm. Mass spectrum APCI m/z 430 (p+1).
Reaction SMILES: N.[Na].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]#[N:13].[N+]([O-])([O-])=O.[NH4+]>[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[C:12]([CH:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:4]=[C:5]2[CH2:10]1)#[N:13]
Reactant: N#CCCc1ccccc1Cl
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Product: N#CC1Cc2ccccc21
Reaction time: 3 h
Yield: 50 %

Procedure:
A 3-liter, three-necked flask equipped with a dry ice condenser, mechanical stirrer and Claisen adapter fitted with an ammonia gas inlet and nitrogen inlet is rinsed with acetone, dried in an oven at 125° C., and heated with an air gun while flushing with nitrogen. The apparatus is cooled in a dry ice-acetone bath and the condenser is filled with a dry ice-acetone mixture. Ammonia gas flow is initiated and 600 ml is condensed out. The ammonia inlet tube is replaced by a stopper, and 0.4 g of powdered iron (III) nitrate is added. Sodium metal, 51.52 g (2.24 moles) is added in small portions over 1 hour. After all the sodium is added, the dry ice bath is removed and cooling is left to the dry ice condenser. Complete conversion of the sodium/ammonia solution to sodamide is indicated by a color change from deep blue to gray. Next, 92.82 g (0.56 mole) of 3-(o-chlorophenyl)propionitrile is added over a period of 10 minutes. The last traces of the nitrile are washed into the flask with small amounts of anhydrous ethyl ether. The dark green reaction mixture is stirred vigorously for 3 hours and then is treated with 134.4 g (1.68 moles) of solid ammonium nitrate. The ammonia is allowed to evaporate overnight at room temperature. Water (420 ml) is cautiously added to the residue. The organic layer is taken up in two 224-ml portions of chloroform, and the solutions are combined and washed twice with 140 ml of aqueous 5 percent hydrochloric acid and once with 140 ml of water. The chloroform solution is dried over anhydrous magnesium sulfate, filtered, and evaporated on a rotary evaporator. The residual liquid is distilled under reduced pressure through an insulated 12-inch Vigreux column. The product is collected at 59° C.-69° C./0.2 mm Hg. The infrared, 'H and 13C nuclear magnetic resonance are run to identify the product. The yield is 50 percent.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([CH2:14][N:8]2[C:7](=[O:12])[CH:6]=[C:5]3[C:10]([N:11]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[CH:9]2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc2ccc(Br)nc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cc3nc(Br)ccc3cc2=O)cc1

Procedure:
The alkylation of 7-bromo-3-hydroxy-8-azaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-(bromomethyl)benzoate (1.53 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). The solid is crystallized from hexanes/ethyl acetate 2:1, the white crystals collected by filtration and dried to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:21]2[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.6 %

Procedure:
6-Chloropyridine-3-sulfonyl chloride (0.318 g, 1.5 mmol; described in: Naegeli, C. et al. Helv. Chim. Acta. 1938, 21, 1746-1750) was added to a suspension of potassium carbonate (0.276 g, 2.0 mmol) in dichloromethane (3 mL) at room temperature. The mixture was stirred for 5 min at 0° C. followed by the addition of tert-butyl 1-piperazinecarboxylate (0.363 g, 2.0 mmol). The resulting reaction mixture was allowed to stir for 16 h at room temperature and the reaction mixture was filtered and the organic solution was concentrated in vacuo. The residue was purified an a silica gel column using heptane/ethyl acetate, (2:1), as the eluent to afford 0.188 g (35% yield) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.74 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 3.53 (t, J=5.2 Hz, 4H), 3.03 (t, J=5.2 Hz, 4H), 1.42 (s, 9H); MS (EI) m/z 362 (M++1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][CH:7]1[CH2:12][CH:11]2[CH2:13][CH:8]1[C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=12.[C:20](Cl)(=[O:22])[CH3:21].O>C(Cl)Cl>[C:20]([CH:12]1[CH:11]2[CH2:13][CH:8]([C:9]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=32)[CH:7]1[O:6][CH3:5])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1C1CC2CC1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1C1CC2C(C(C)=O)C1OC

Procedure:
23.5 g of aluminum chloride are added in small portions to a mixture of 30 g of 1,4-dimethoxybenzonorbornene and 13.8 g of acetyl chloride in 300 cm3 of methylene chloride. At this stage, a check is made that all the starting material has been converted. The reaction mixture is poured into 300 cm3 of water. The organic phase is washed with sodium bicarbonate, then with water, and dried over magnesium sulphate.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:19]1[S:21][CH2:20]1>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:19][CH2:20][SH:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CS1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: SCCC1c2ccccc2-c2ccccc21
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
A solution of fluorene (20.0 g; 120 mmol) in THF (200 mL) was cooled to -40° C. and treated with 48 mL of a 2.5M solution of n-butyllithium in hexanes (120 mmol). After stirring for 15 minutes, a solution of ethylene sulfide (6.5 mL; 109 mmol) in 30 mL of THF was added, and the resulting mixture was stirred at -40° C. for 30 minutes and room temperature for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride, the layers were separated, and the organic phase was washed with 10% HCl, dried and concentrated. The crude product was purified on a flash column, eluting with hexane, to provide 16.8 g (62%) of the product as an oil that recrystallized from hexane as a white solid, mp 38°-40° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:18]([NH:20][CH3:21])=[O:19])[CH2:13]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=1[CH3:42])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:30][C:31]([NH:33][C:34]3[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=3[CH3:42])=[O:32])[CH:14]([C:18]([NH:20][CH3:21])=[O:19])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Reactant: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(C)cc(C)cc1C
Yield: 51.5 %

Procedure:
A mixture of 5.8 g of 4-[4,4-bis(4-fluorophenyl)butyl]-N-methyl-2-piperazine-carboxamide, 3.6 g of 2-chloro-N-(2,4,6-trimethylphenyl)acetamide, 2.12 g of sodium carbonate and 150 ml of MIK is stirred and refluxed for 18 hours. The reaction mixture is cooled and washed with water. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dried, yielding 4.34 g of 4-[4,4-bis(4-fluorophenyl)butyl]-2-[(methylamino)carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide (compound 2, mp. 90.2° C.).
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)#[N:4]>CCO.O>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:20][CH:21]=1
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Reactant: NO
Solvent: CCO
Solvent: O
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A 50% aqueous solution of hydroxylamine (13.25 mL, 225 mmol) was added at once into a solution of tert-butyl N-(4-cyanobenzyl)-N-methylglycinate (11.70 g, 45 mmol) in EtOH (75 mL). The reaction mixture was stirred at RT overnight. The solvents were removed under reduced pressure to give a white solid. The solid was suspended in water (200 mL) and stirred for 20 minutes, then filtered off, washed with water and dried to give the title compound as a white powder (12.54 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 9.58 (s, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 5.78 (s, 2H), 3.62 (s, 2H), 3.15 (s, 2H), 2.24 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 294.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[CH:8]=[C:7]3[O:13][CH2:14][O:15][C:6]3=[CH:5][C:4]=2[N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CN1C(=O)CCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[CH:8]=[C:7]4[O:13][CH2:14][O:15][C:6]4=[CH:5][C:4]=3[N:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Nc1nc(Cl)nc2cc3c(cc12)OCO3
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(N)c3cc4c(cc3n2)OCO4)CC1
Yield: 39 %

Procedure:
A mixture of 6-chloro-[1,3]dioxolo[4,5-g]quinazolin-8-ylamine (0.9 g, 4.02 mmol equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.61 g, 8.05 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.6 g (39%) of the title compound. MS (ISP): 388.4 [M+H]+.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+].C([Li])CCC.CCCCCC.[C@@H:28]12[C:37](=[O:38])[O:36][C:34](=[O:35])[C@@H:29]1[CH2:30][CH2:31][CH2:32][CH2:33]2>O.C(OCC)C.O1CCCC1>[N:6]1[CH:7]=[CH:8][C:3]([C:37]([C@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[C:34]([OH:36])=[O:35])=[O:38])=[CH:4][CH:5]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(c1ccncc1)[C@H]1CCCC[C@H]1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Bromopyridine hydrochloride (10.05 g, 51.8 mmol) was treated with potassium carbonate (7.15 g, 51.8 mmol) in water (50 mL), and the resulting solution was saturated with sodium chloride. The 4-bromopyridine free base was extracted with diethyl ether, and the solution was stored under N2 over 3 angstrom molecular sieves for 1 h. The 4-bromopyridine solution was slowly transferred by cannula to a stirred solution of 2.5 M butyllithium in hexane (21.2 mmL, 53 mmol) in anhydrous diethyl ether (100 mL), maintained at −78° C. under N2. The reaction mixture was stirred for 30 min., and then a solution of cis-1,2-cyclohexanedicarboxylic anhydride (8.33 g, 54 mmol) in anhydrous tetrahydrofuran (150 mL) was added by cannula. The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to 20° C. The reaction mixture was quenched by addition of water (200 mL), and the aqueous layer was separated and acidified to pH=4 by addition of 6 M hydrochloric acid. The aqueous layer was saturated with sodium chloride and extracted with a (1:1) mixture of ethyl acetate and tetrahydrofuran (400 mL). The organic layer was washed with sat. NaCl, dried over MgSO4, filtered, and evaporated to give cis-2-(4-pyridylcarbonyl)cyclohexanecarboxylic acid, as a solid, which was used immediately in the next step.
Reaction SMILES: C([O:4][CH:5]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[N:7]2[CH:24]=[N:25][N:26]=[C:6]12)(=O)C.[OH-].[Na+].C(O)(=O)C>C(O)C>[OH:4][CH:5]1[C:11](=[O:12])[N:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[N:7]2[CH:24]=[N:25][N:26]=[C:6]12
Reactant: CC(=O)OC1C(=O)N(c2ccccc2)c2cc(Cl)ccc2-n2cnnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1C(O)c2nncn2-c2ccc(Cl)cc2N1c1ccccc1

Procedure:
3.5 g of 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 2.8 ml of 4 N aqueous sodium hydroxide in 160 ml of ethanol are stirred overnight at 25°. The reaction is neutralized with 0.5 g of acetic acid and the solvent is evaporated. The residue is partitioned between chloroform and water, the organic phase is dried and the solvent evaporated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([N:21]3[CH:25]=[C:24]([C:26]4[C:27]5[CH:34]=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH:23]=[N:22]3)[CH2:18][C:19]#[N:20])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:35][N:36](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:19]([CH2:18][CH:17]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:35]#[N:36])=[CH:7][N:6]=2)=[O:9])[CH2:11][CH2:12]1)#[N:20]
Reactant: N#CCC(CN1CCN(C(=O)c2ccc(Br)cn2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cn2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 150 °C

Procedure:
Zinc cyanide (24 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.014 mmol) were added to a solution of 4-{4-[(5-bromopyridin-2-yl)carbonyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (15 mg, 0.029 mmol) in N,N-Dimethylformamide (0.48 mL). The mixture was degassed, then heated in the microwave at 150° C. for 15 minutes. The mixture was diluted with MeCN (1 mL), filtered and purified via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH (9 mg, 67%). 1H NMR (400 MHz, d6-dmso): δ □12.12 (br s, 1H), 9.03 (dd, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.43 (dd, 1H), 8.37 (s, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.99 (tt, 1H), 3.62-3.56 (m, 2H), 3.27-3.19 (m, 4H), 2.86 (dd, 1H), 2.82 (dd, 1H), 2.64-2.56 (m, 1H), 2.53-2.41 (m, 2H), 2.39-2.31 (m, 1H); LCMS (M+H)+: 467.3.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>C(O)C>[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Oc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25.0 mg, 0.0464 mM), then 3-hydroxy-benzaldehyde (6.2 mg, 0.051 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (19.2 mg, yield: quantitative).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19](=[O:20])[CH2:18][N:17]([CH2:21][C@H:22]([NH:31]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C@@H:23]2[CH2:27][C@@H:26]([CH2:28][CH3:29])[C:25](=[O:30])[O:24]2)[C:16]([CH3:45])([CH3:44])[CH2:15]1.C1(S)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:58](OC(OC(C)(C)C)=O)([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59].N[C@H]([C@@H]1C[C@@H](CC)C(=O)O1)CN1C(C)(C)CN(C2C=CC=CC=2Cl)C(=O)C1>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:61]([O:60][C:58](=[O:59])[NH:31][C@H:22]([C@@H:23]1[CH2:27][C@@H:26]([CH2:28][CH3:29])[C:25](=[O:30])[O:24]1)[CH2:21][N:17]1[CH2:18][C:19](=[O:20])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[Cl:7])[CH2:15][C:16]1([CH3:45])[CH3:44])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC[C@@H]1C[C@@H]([C@@H](N)CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)OC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
1.00 g of cesium carbonate (3.08 mmol) was added to a solution of 1.49 g of N—{(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (106h) (2.57 mmol) and 0.52 ml of thiophenol (content: 95%) (5.14 mmol) in N,N-dimethylformamide (13 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=50/1-10/1). 235 mg of sodium bicarbonate (2.80 mmol) and 610 mg of di-t-butyl dicarbonate (2.80 mmol) were added to a solution of 4-{(S)-2-amino-2-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}-1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained above in ethyl acetate (12 ml)-water (12 ml), and the mixture was stirred at room temperature for 2.5 hours. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=2/1-1/1) to obtain 1.11 g of the title compound (yield: 88%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1S(C)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
3-(3-cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (138 mg) was dissolved in N,N-dimethylformamide (1 mL), and lithium chloride (58 mg) was added to the solution, and then the mixture was stirred at 70° C. for 3 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (69 mg) as a brown crystal.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([F:10])[C:6]([Cl:9])=[N:7][CH:8]=1.C1N2CN3CN(C2)CN1C3.C([O-])(O)=[O:22].[Na+]>C(O)(=O)C.O>[Cl:9][C:6]1[C:5]([F:10])=[CH:4][C:3]([CH:2]=[O:22])=[CH:8][N:7]=1
Reactant: O=C([O-])O
Reactant: Fc1cc(CBr)cnc1Cl
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(bromomethyl)-2-chloro-3-fluoropyridine (2.0 g, 8.91 mmol) and hexamethylenetetramine (2.75 g, 19.6 mmol) in 50% aqueous acetic acid (53 ml) was heated to reflux. After 1 hour, the mixture was cooled to room temperature, neutralized carefully with solid NaHCO3 (73.7 g), diluted with water (400 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated on a rotary evaporator and purified by silica gel column chromatography (hexane/ethyl acetate) to afford 6-chloro-5-fluoronicotinaldehyde as pale-yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.12 (d, J=2.4 Hz, 1H), 8.72 (d, J=1.6 Hz, 1H), 7.94 (dd, J=2.0, 8.0 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −116.3.