Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:24])=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].O.[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:24])=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1cccc(NC(=O)CNc2ccc(F)c(F)c2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(NC(=O)CNc2ccc(F)c(F)c2)cccc1C(=O)O

Procedure:
A mixture of the product from step (c) (1.33 g) and lithium hydroxide monohydrate (0.84 g) in methanol (120 ml) and water (25 ml) was heated at reflux for 2 hours, cooled and concentrated in vacuo. The residual aqueous solution was acidified with glacial acetic acid and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to give a cream solid. Yield 1.27 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[C:3]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Br[C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH:32]([CH3:51])[N:33]([C:37]3[CH:42]=[C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[N:40]=[C:39]([NH2:50])[N:38]=3)[CH2:34]2)=[CH:29][CH:28]=1>>[NH2:50][C:39]1[N:38]=[C:37]([N:33]2[CH:32]([CH3:51])[CH2:31][C:30]3[C:35](=[CH:36][C:27]([C:5]4[CH:4]=[C:3]([C:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[O:17])[N:2]([CH3:1])[CH:6]=4)=[CH:28][CH:29]=3)[CH2:34]2)[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[N:40]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Product: CC1Cc2ccc(-c3cc(C(=O)OCc4ccccc4)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 7 starting from benzyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Example 87A, Step 6) and 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Peak 2, Example 49, Step 7). LCMS (M+H)+: m/z=552.1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:21]([O:25][C:26]([N:28]([C:45]1[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=1)[S:29]([C:32]1[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)=[N:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:27])[CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([C:33]2[C:32]([S:29]([N:28]([C:26]([O:25][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:27])[C:45]3[C:50]([O:51][CH3:52])=[N:49][C:48]([CH3:53])=[CH:47][N:46]=3)(=[O:31])=[O:30])=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:39][CH:40]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CBr)cc1
Yield: 70.5 %

Procedure:
N-Bromosuccinimide (2.99 g) and azobisisobutyronitrile (275 mg) were added to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylphenyl)pyridine-3-sulphonamide (7.9 g) in carbon tetrachloride (150 ml) and the mixture was heated under reflux for 4 hours. Insoluble material was removed by filtration and the fitrate was concentrated by evaporation. The residue was redissolved in ethyl acetate (200 ml) and the solution was washed with water (100 ml) and saturated sodium chloride solution (100 ml). The solution was dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ethyl acetate/hexane (3:7 v/v, 80 ml) to give 2-(4-bromomethylphenyl)-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-pyridine-3-sulphonamide (6.5 g), m.p. 125-128° C.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[CH3:14].C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:15][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[CH2:14][Br:23]
Reactant: Cc1cc(S(C)(=O)=O)ccc1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(OC(F)F)c(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of sulfone 15 from above (0.92 g) dissolved in CCl4 (20 mL) was added NBS (0.83 g) and a catalytic amount of benzoyl peroxide and the resulting mixture was irradiated with a sum lamp under reflux for 4 hours. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated. The crude product was purified by silica gel chromatography. Eluting with ethyl acetate/hexanes (1:5) furnished 2-difluoromethoxy-5-methanesulfonylbenzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=1.[Cl:24]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:11]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][C:10]=1[CH:22]=[O:23]
Reactant: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (331 mg) in N,N-dimethylformamide (33 mL) was added N-chlorosuccinimide (268 mg) and the mixture was stirred at 60° C. for 1 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 250 mg, 68%).
Reaction SMILES: C([N:4]1[CH:9]=[CH:8][C:7](=[CH:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:5]1)(=O)C>C(O)C>[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1
Reactant: CC(=O)C=C1C=CN(C(C)=O)C=C1
Solvent: CCO
Product: CC(=O)Cc1ccncc1
Yield: 98.3 %

Procedure:
To 20 g of 1-acetyl-4(acetylmethylidene)-1,4-dihydropyridine was added 30 ml ethanol and the mixture refluxed 4 to 8 hours. Upon removal of solvent, 15 g of 1-(4-pyridinyl)-2-propanone was obtained as a light yellow oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.[C:23]1([CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[OH:24]>C(O)CCC.[Na].[Hg]>[CH2:21]([O:24][C:23]1[CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: Oc1ccc(O)cc1
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Hg]
Agent: [Na]
Solvent: CCCCO
Product: C=CCCCCCCCCCOc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 7 h
Yield: 47.6 %

Procedure:
2.60 g (8.02 mM) of 10-undecenyl p-toluenesulfonate and 1.79 g (16.2 mM) of hydroquinone were well mixed with 3 ml of butanol under stirring. Into the solution, a solution of 0.419 (9.74 mM) of sodium amalgam dissolved in 6 ml of butanol, followed by 7 hours of heat-refluxing at 110° C. After the reaction, butanol was distilled off, followed by addition of water and extraction with ether. To the ether extract liquid was added anhydrous sodium sulfate for drying, followed by distilling-off of ether and purification by column chromatography (developer solvent: methylene chloride) to obtain 1.00 g (3.82 mM) of p-(10-undecenyl)oxyphenol. Yield: 47.6%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:39]=[CH:38][C:13]([O:14][C:15]3[C:16]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:17]=4[S:18][C:19]=3[C:20]3[CH:25]=[CH:24][C:23]([S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:40]([O:43]CC)(=[O:42])C>C(OCC)C>[F:32][C:29]([F:30])([F:31])[C:40]([OH:43])=[O:42].[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15]3[C:16]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:17]=4[S:18][C:19]=3[C:20]3[CH:21]=[CH:22][C:23]([S:26]([C:29]([F:30])([F:31])[F:32])(=[O:27])=[O:28])=[CH:24][CH:25]=3)=[CH:38][CH:39]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Agent: O=S(=O)(c1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)C(F)(F)F

Procedure:
Dissolve the compound of Example 96 (100 mg, 0.17 mmol) in ethyl acetate (2 mL), dilute with diethyl ether (10 mL) and place in an ice bath. Immediately add 2M HCl in diethyl ether (0.13 mL) and collect the solids on filter paper. Purify by preparative HPLC to yield 37 mg of the title compound (29%): mass spectrum (ion spray): m/z=578 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1>CO.C1COCC1.[OH-].[Pd+2].[OH-].[C]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.6 %

Procedure:
Oxazolyl chloride (4.0 mL, 45.9 mmol) and several drops of DMF were added to a solution of dichloromethane (5 mL) containing 4-benzyloxybenzoic acid (2.29 g, 10.0 mmol) under ice-cooling, and then dichloromethane (2.5 mL) was further added thereto. The mixture was stirred at room temperature for 2.5 hours, and the solvent was evaporated. The resulting residue was dissolved in dichloromethane (20 mL), and glycine methyl ester hydrochloride (1.39 g, 11.1 mmol) and N-ethyl-N,N-diisopropylamine (4.4 mL, 25.2 mmol) were added thereto under ice-cooling. The mixture was stirred at room temperature for 18 hours, and then water was added thereto to terminate the reaction. The mixture was extracted with dichloromethane, and the organic layers were combined and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:4 to 0:1, v/v) to give N-[4-(benzyloxy)benzoyl]glycine methyl ester. Then, 1.66 g of this ester was dissolved in a solvent mixture of methanol (8 mL) and THF (8 mL). To the resulting mixture, 20% palladium hydroxide-carbon (168 mg) was added. The mixture was vigorously stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite and then concentrated to give 1.19 g of the title compound (white powder, yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:24][CH:23]=[CH:22][C:5]=2[C:6](S(C(F)(F)F)(=O)=O)=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14].[Li][CH3:26]>[Zn](Br)Br.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:24][CH:23]=[CH:22][C:5]=2[C:6]([CH3:26])=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14]
Reactant: [Li]C
Reactant: COc1c2occc2c(S(=O)(=O)C(F)(F)F)c2c(=O)cc(C)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Br[Zn]Br
Solvent: O
Product: COc1c2occc2c(C)c2c(=O)cc(C)oc12
Yield: 70 %

Procedure:
9-Methoxy-7-methyl-4-trifluoromethanesulfonyl-5H-furo[3,2-g]chromen-5-one (324 mg, 1.0 mmol), ZnBr2.H2O (1.04 g, 4.0 mmol), CuI (28 mg, 0.15 mmol), PdCl2(PPh3)2 (84 mg, 0.12 mmol) and MeLi (2.5 ml of 1.6 M in diethylether, 4.0 mmol) were treated as described under General Procedure G (Step 2) to afford the title compound (Yield 70%). 1H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H, Me), 2.94 (s, 3H, Me), 4.21 (s, 3H, OMe), 6.05 (s, 1H), 6.91 (d, J=2.4, 1H), 7.65 (d, J=2.4, 1H). MS (ES) m/z: 244.9 (M+H+).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:20]=1)[NH2:18]>C(O)(=O)C>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26]([O:25][C:21]2[N:20]=[C:19]([N:17]=[N:18][C:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:12]=3[OH:16])[CH:24]=[CH:23][CH:22]=2)=[CH:27][CH:28]=1
Reactant: NNc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Product: Oc1c(N=Nc2cccc(Oc3ccc(C(F)(F)F)cc3)n2)c2ccccc2c2ccccc12
Temperature: 100 °C

Procedure:
Then, a reaction flask was loaded with acetic acid (30 ml) and 9,10-phenanthrenequinone (2.0 g), and the temperature was raised to 100° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 2-hydrazino-6-(4-trifluoromethylphenoxy)pyridine (3.0 g) was added in 15 minutes. After stirring at 95 to 105° C. for two hours, the reaction mixture was filtrated. The filtrated crystals were successively washed with hot water and hot methanol, followed by recrystallization with dioxane-water to give crystals, which were then filtrated and dried to give intended crystals (3.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22]>>[CH3:19][N:20]([CH3:24])[C:21](=[S:22])[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)C(=S)Cl
Product: CN(C)C(=S)Oc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 83.8 %

Procedure:
Following the procedure described in Preparation I and starting from 18 g (0.07407 mol) of 4-hydroxyphenyl 3-nitrophenyl methanone and 12.3 g (0.0992 mol) of dimethylthiocarbamoyl chloride, 20.5 g (yield: 84%) of O-4-(3-nitrobenzoyl)phenyl dimethylthiocarbamate are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+].C(OCC)(=O)C.Cl>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:32][C:30](=[O:33])[CH3:31])[CH2:10][C@H:9]1[CH2:18][N:19]1[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]2[C:23]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CC([O-])=S
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (3 g) in dimethylformamide (30 ml), potassium thioacetate (1.65 g) is added. The mixture is stirred at 60° C. for 3.5 hours. The reaction mixture is poured into a mixture of ethyl acetate and dilute hydrochloric acid. The organic layer is taken, washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (2.12 g). Yield: 74%. Orange colored syrup.
Reaction SMILES: O.NN.[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO>[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCc1ccccc1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Hydrazine monohydrate (0.36 g, 7.2 mmol) was added to a solution of 2-(5-phenylpentyl)isoindoline-1,3-dione (0.68 g, 2.3 mmol) in 25 mL of EtOH. The solution was stirred under reflux for 5 hrs and then cooled to room temperature. The white precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in a 1N solution of NaOH (80 mL) and extracted with chloroform (3×70 mL). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (solid deposition with TEA, eluent: 20% MeOH in dichloromethane with 1% of TEA) to afford the title compound (0.28 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.37-1.48 (m, 2H), 1.58-1.72 (m, 4H), 2.57-2.69 (m, 2H), 3.29 (t, J=6.70 Hz, 2H), 7.13-7.24 (m, 3H), 7.26-7.34 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:8][CH2:9][N:10]([CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:58])C(=O)C1>CN(C=O)C>[Cl:58][C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[N:10]([CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:36][CH2:37]2)[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:18][C:17]=1[C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCN(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)c(Cl)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-(2-(1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)ureido)ethyl)piperidine-1-carboxylate (0.35 g, 0.49 mmol) in DMF (10 ml) was added NCS (0.065 g, 0.49 mmol). The resulting mixture was stirred overnight at room temperature. After this time the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and sat. aq. NaHCO3. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the crude product as a thick yellow oil. This crude product was purified by combi-flash (10-50% EtOAc/hexane). To give tert-butyl 4-(2-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)ethyl)piperidine-1-carboxylate 50 as a yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][S:16][C:17]2[C:22]([C:23]3[O:27][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][N:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:8][C:9]1[CH:14]=[C:13]([CH2:15][S:16][C:17]2[C:22]([C:23]3[O:27][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][N:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CSc2ncccc2-c2nnc(Nc3ccccc3)o2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(CSc2ncccc2-c2nnc(Nc3ccccc3)o2)ccn1

Procedure:
To a solution of 5-(2-(2-t-butoxycarbonylaminopyridin-4-yl) methylthiopyridin-3-yl)-N-phenyl-1,3,4-oxadiazol-2-amine (140 mg, 0.30 mmol; Compound 1-(7)) in dioxane (1.0 mL) was added a 4M dioxane solution of hydrogen chloride (1.0 mL, 4.0 mmol) at room temperature and then the mixture was stirred over night. The precipitated solid was filtered off to give 130 mg (quantitative) of the titled compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH:11][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10].[OH-].[Na+]>>[CH2:8]([N:11]([CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:10]
Reactant: Clc1ccncc1
Reactant: C=CCNCC=C
Agent: [Na+]
Agent: [OH-]
Product: C=CCN(CC=C)c1ccncc1

Procedure:
4-Chloropyridine (13.24 g) was refluxed with excess diallylamine (28.40 g) under a nitrogen atmosphere for 3 days. The product mixture was neutralized with aqueous NaOH and extracted with ether. After drying, the ether was removed by simple distillation and the product purified by fractional distillation under reduced pressure. The pure 4-(diallylamino)pyridine (DAAP) was characterized by elemental analysis, FTIR, 13C NMR, and GC.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:33]#[N:34]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:3]5[CH:2]=[CH:11][N:34]([CH2:26][C:7]6[CH:6]=[CH:5][CH:10]=[CH:9][N:8]=6)[N:33]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: N#N
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3ccn(Cc4ccccn4)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The residue was dissolved in 1,4-dioxane (0.50 mL) and water (0.10 mL). To the solution was added 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.018 g, 0.043 mmol, Peak 1, Example 49, Step 7), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.916 mg, 0.00129 mmol), sodium carbonate (9.14 mg, 0.0862 mmol). and the mixture was vacuumed and refilled with N2 for 3 times. The reaction was stirred at 90° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=496.3.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C@@H:17]([C:19]1[CH:30]=[CH:29][C:22]2[O:23][C:24]([CH3:28])(C)[O:25][CH2:26][C:21]=2[CH:20]=1)[OH:18].C(O)(=[O:38])C>O>[C:24]([O:23][C:22]1[CH:29]=[CH:30][C:19]([C@@H:17]([OH:18])[CH2:16][NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[C:2]([Cl:1])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[CH:20][C:21]=1[CH2:26][OH:25])(=[O:38])[CH3:28]
Reactant: CC(=O)O
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3c(Cl)cccc3Cl)ccc2O1
Solvent: O
Product: CC(=O)Oc1ccc([C@@H](O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl)cc1CO
Reaction time: 0.5 h

Procedure:
A solution of (1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (130 mg) in acetic acid (2 ml) and water (1 ml) was heated (oil bath temperature 80°) with stirring for 30 min. The mixture was cooled to 20° and the solvent was evaporated in vacuo. The residue was azeotroped in vacuo with MeOH (2×1 ml) to give the title compound (135 mg). LCMS RT=2.57 min, ES+ve 486 (MH)+, 488 (MH)+, 490 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>>[NH:21]1[CH:22]=[N:23][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[N:20]1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: Sc1nc[nH]n1
Product: O=c1ccc2cc(OCCCCSc3nc[nH]n3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril and 3-mercapto-1,2,4-triazole.