Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CN(C)C=O.[Br:12][C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([OH:17])=O>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([C:13]1[CH:21]=[CH:20][C:19]([CH2:1][CH3:2])=[CH:18][CH:14]=1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)ccc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(I)ccc2Br)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Oxalyl chloride (9 mL) and dimethylformamide (0.5 mL) are added to a mixture of 2-bromo-5-iodo-benzoic acid (25 g) in dichloromethane (80 ml). The reaction mixture is stirred for 14 h at room temperature, then filtered and separated from all volatile constituents in a rotary evaporator. The residue is dissolved in dichloromethane (50 mL) and ethyl-benzene (23 mL) and the resultant solution is cooled to −5° C. Then aluminum trichloride (12.5 g) is added batchwise so that the temperature maintains below 10° C. The solution is warmed slowly to room temperature and stirred overnight. The solution is poured onto crushed ice, the organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with hydrochloric acid (1 mol/l), sodium hydroxide solution (1 mol/l) and with brine. The organic phase is dried over sodium sulphate and the solvent is removed to give the product as an oil that crystallizes on standing.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH2:18][CH2:19][CH2:20][OH:21])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][S:2]([O:21][CH2:20][CH2:19][CH2:18][C:7]1([CH3:6])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CCCO)Cn2cc([N+](=O)[O-])nc2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CCCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Methanesulfonyl chloride (1.4 ml, 18.09 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of 2-methyl-2-(3-hydroxypropyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 38 (2.1 g, 9.24 mmol), triethylamine (2.8 g, 20.09 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and methylene chloride (80 ml) with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was concentrated. 10% hydrochloric acid was added to the residue, and the resulting mixture was stirred for 30 minutes with cooling on ice-bath. The precipitates were filtered off and washed with water to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl methanesulfonate (2.6 g, yield 92%) as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:10]=2)=O)[CH:2]=1.[Cl-].[OH:27][NH3+:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:28][OH:27])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:10]=2)[CH:2]=1
Reactant: O=C(c1cccnc1)c1cccc(NS(=O)(=O)c2ccc(Cl)cc2)c1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: O=S(=O)(Nc1cccc(C(=NO)c2cccnc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.45 g (20 mmol) of the compound from Example 1, 2.08 g (30 mmol) of hydoxylammonium chloride and 4.14 g (30 mmol) of potassium carbonate are refluxed in 20 ml of ethanol for 15 h. After cooling to room temperature, the mixture is evaporated and the residue is stirred in 50 ml of water for 3 h (after this time no oily residues, but only crystalline residues, were still undissolved). The precipitate was filtered off, washed with water and recrystallised from methanol by addition of water. Yield: 5.71 g (73.7% of theory) M.p.: 170° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[C:19]([N:21]=[CH:22]OCC)#[N:20].Cl.C(O)C>C(O)C>[C:19]([NH:21][CH:22]=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])#[N:20]
Reactant: CCOC=NC#N
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1[nH]cnc1CSCCN=CNC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4.88 g of 2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethanamine (prepared according to British Pat. No. 1,338,169 which is hereby incorporated by reference,) in 75 ml of absolute ethanol, are added 5.55 ml of triethylamine. Then 1.96 g of ethyl N-cyano-formimidate in 15 ml of ethanol are added dropwise under stirring and at room temperature (prepared according to Huffman and Schaefer "J.Org.Chem.",28, 1816, 1963). Stirring is continued for 1 hour, after which are added 2.5 ml of 8N HCl/ethanol. A white solid is separated, which is subsequently crystallized in ethanol, filtered off and dried in a vacuum dessicator in the presence of phosphorus pentoxide and sodium hydroxide. 2.9 g of N-cyano-N'-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]formamidine are obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]([Cl:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[ClH:18].[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:14]=1[O:13][CH3:12])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NC2CN3CCC2CC3)c(OC)c1
Yield: 23.7 %

Procedure:
A mixture of 3-aminoquinuclidine dihydrochloride, 6.95 g, (0.349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in diethyl ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211°-212° C. The NMR analysis was satisfactory.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(C(=O)NNC(=O)[C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)o2)cc1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
The crude material from the reaction immediately preceding (Intermediate 2a) N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-methoxy benzohydrazide (330 mg, 0.79 mmol) was added to THF (40 mL) and stirred at room temperature. PS-BEMP (1.08 g, 2.37 mmol base) was added to the solution followed by slow addition of p-TSCl (166 mg, 0.87 mmol). The reaction mixture was stirred for 3 hand the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed on silica gel with Hex:EtOAc (6:4) to get the purified product (130 mg, 41%). 1H NMR (500 MHz, Acetone-d6, δ in ppm) 7.93 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 1H), 7.11 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 1H), 5.68 (d, J=9 Hz, 1H), 5.07 (m, 1H), 4.79 (m, 1H), 4.60 (m, 1H), 3.89 (s, 3H), 2.40 (s, 3H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(N)cc1C(=O)O
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O

Procedure:
A mixture of 11.7 g. (0.054 mole) of 2-phenacylcyclohexanone, 10.5 g. (0.054 mole) of 2-acetamido-5-aminobenzoic acid, and 50 ml. of glacial acetic acid was heated under reflux for 4 hours, cooled, diluted with 15 ml. of methanol and filtered. The collected solid was recrystallized from acetonitrile to provide 9.45 g. (47%) of crystals, m.p. 192° -194°.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH:9]([C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=2)[C:10](O)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ON1C2C=CC=CC=2N=N1.C>CO.C(Cl)Cl>[CH2:28]([NH:35][C:10](=[O:11])[CH:9]([NH:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:13]1[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:16]([OH:23])=[C:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:14]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)c1cc(C(NCC2CCCCC2)C(=O)O)cc(C(C)(C)C)c1O
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(NCC2CCCCC2)C(=O)NCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.4 %

Procedure:
To a methylene chloride (5 mL) solution of Example 22 (0.36 g, 0.96 mmol) was added benzyl amine (110 mg, 1.0 mmol), N,N1 -dicyclohexylcarbodiimide (DCC) (206 mg, 1.0 mmol), and 1-hydroxybenzotriazole (HOBT) (135 mg, 1.0 mmol). The solution was stirred at room temperature for 24 hours. The mixture was filtered free of insolubles and the filtrate evaporated to give an oil. The oil was dissolved in methanol (30 mL) treated with charcoal and evaporated to a foam. The foam was dissolved in ethyl acetate (75 mL) and washed with saturated sodium bicarbonate (50 mL) and then dried over magnesium sulfate. This was purified by chromatography (125 g silica gel, 2% methanol in methylene chloride). The appropriate fractions were combined and evaporated in vacuo to give 0.10 g (22%) of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20](O)=[O:21])=[CH:5]2.[CH2:23]([S:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:23]([S:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:20]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(CN)SCc1ccccc1
Reactant: O=C(O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a mixture of 5-fluoro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.20 g), 2-(benzylthio)-2-methylpropylamine (0.13 g), 1H-1,2,3-benzotriazol-1-ol (0.11 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (220 mg, crude yield 72%) as pale-purple crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][S:4]1(=[O:21])=[O:20])[CH3:2].O.NN>CCO>[CH2:1]([N:3]1[CH2:7][CH:6]([CH2:8][NH2:9])[CH2:5][S:4]1(=[O:21])=[O:20])[CH3:2]
Reactant: CCN1CC(CN2C(=O)c3ccccc3C2=O)CS1(=O)=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN1CC(CN)CS1(=O)=O
Yield: 53.5 %

Procedure:
To a solution of 2-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-isoindole-1,3-dione (261 mg, 0.85 mmol) in EtOH (4 ml) was added hydrazine monohydrate (0.165 ml, 4 equiv). The reaction mixture was then refluxed overnight and a white gum formed. The reaction mixture was filtered (rinsing several times with EtOH) and the filtrate was evaporated to afford 81 mg of the expected amine contaminated by 10% of 2,3-Dihydro-phthalazine-1,4-dione. It was used as such in the next step.
Reaction SMILES: [C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=[S:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:21][CH:13]1[CH:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14]1
Reactant: S=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)CCCSC1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 75 mg (0.26 mmol) of 3-naphthalen-1-ylmethyl-imidazo[1,2-a]pyridine-2-thione and 70 mg (0.39 mmol) of methyl 4-bromobutyrate and 72 mg (0.52 mmol) of potassium carbonate in 3 mL of 50% acetone in dichloromethane is stirred at room temperature for 18 h. The mixture is concentrated in vacuo and the residue is purified by flash chromatography on silica gel eluting with 50˜75% ethyl acetate in hexanes to give the desired compound.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[N:30]=1>CN(C)C=O>[Cl:28][C:29]1[N:30]=[C:31]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: ClCc1cccc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(Cl)n3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (36.3 mg, 0.22 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (39.5 mg, 90%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.O(CCCCCCCBr)C1C=CC=CC=1>>[C:1]1([S:7][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: BrCCCCCCCBr
Agent: BrCCCCCCCOc1ccccc1
Product: BrCCCCCCCSc1ccccc1
Yield: 46 %

Procedure:
7-Phenylthioheptyl bromide was prepared from thiophenol (4.40 g, 40 mmol) and 1,7-dibromoheptane (10.32 g, 40 mmol) as described above for 7-phenoxyheptyl bromide. Yield: 46% bp; 132°-136° C./0.05 torr; 1H-NMR: 1.30-1.85 (m, 10H), 2.90 (t, 2H), 3.35 (t, 2H), 7.25 (s, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[C:21](=[O:31])[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:11][C:8]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:19][C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=1)[CH2:9][CH3:10]
Reactant: Cn1c(=O)c(CBr)cc2ccccc21
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(OC)(c1cccc(OCc2cc3ccccc3n(C)c2=O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (0.5 g, 2 mmol), 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one (0.5 g, 2 mmol), potassium carbonate (0.35 g, 2.5 mmol) and dimethylformamide (3 ml) was stirred at ambient temperature for 48 hours. The mixture was filtered, the filtrate was added to water (30 ml) and the mixture was extracted with ethyl acetate (3×15 ml). The organic extracts were combined, washed with a dilute aqueous sodium hydroxide solution and with a saturated sodium chloride solution, dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with toluene/ethyl acetate (7/3 v/v) to give 2-[1-methoxy-1-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-3-ylmethoxy)-phenyl]propyl]thiazole (0.84 g, 100%), m.p. 123°-125° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C@H:5]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:41])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][C:30]=1[O:39][CH3:40].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:41])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:6]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[O:37])=[CH:31][C:30]=1[O:39][CH3:40]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-methyl-2-(S)-pirrolidinylmethoxy]benzoate (141 mg, 0.57 mmol), 4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (178 mg, 0.57 mmol) and N,N-dimethylaminopyridine (69.0 mg, 0.57 mmol) in DMF (10 ml) was added EDC.HCl (120 mg, 0.62 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc as eluent to give methyl 4-[1-[4-[N′-(2-methylphenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (297 mg, 96%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 1.24–1.34 (m, 3 H), 1.93–2.18 (series of m, 4 H), 2.28 (s, 3 H), 3.65 (s, 3 H), 3.88 (s, 3 H), 3.62–3.87 (m, 3 H), 4.11–4.38 (series of m, 3 H), 6.42–8.06 (series of m, 13 H); MS (ESI) m/z, 546 (M++H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[O-]S([O-])(=O)=O.[Ca+2].[F:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:23]1[C:27]2[NH:28][CH:29]=[N:30][C:31](=O)[C:26]=2[CH:25]=[N:24]1.CN(C)C=O>CC(C)=O>[Cl:3][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:23]([C:14]3[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:13]=3[F:12])[N:24]=[CH:25][C:26]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(=O)nc[nH]c32)c(F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Temperature: 130 °C
Yield: 89.7 %

Procedure:
POCl3 (379.1 g, 2.59 mol) was transferred under nitrogen to a 1 L round bottom flask fitted with a mechanical stirrer, a condenser and a tube connected above the condenser filled with a drying agent (drierite). 1-(2-Fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (4) (100 g, 0.324 mol) was added to the reaction vessel, the contents were stirred, and a slurry was obtained. Dimethylformamide (DMF; 9.43 g, 0.129 mol) was added, and the reaction mixture was heated to reflux (oil bath set at 130° C.). After refluxing for 3 h, an additional amount of DMF (9.43 g, 0.129 mol) was added. The resulting mixture was refluxed for another 2 h and then gradually cooled to 55° C. Subsequently, acetone (270 mL) was added. The mixture was further cooled to 23° C. and a precipitate was obtained, which was isolated by filtration. The filtrate was quenched by slow dropwise addition into ice water (1.5 L) with stirring. During the quench, the internal temperature was kept at 0° C. or below by cooling with an ice-salt bath. Product 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) crystallized out of the quenched mixtures was isolated by filtration. The solids from both filtrations were combined and washed with water (2×500 mL), 10% aqueous NaHCO3 (2×500 mL), and water (2×500 mL) until the filtrate was neutral. The washed solids were vacuum dried overnight at room temperature and dissolved in methylene chloride (600 mL). The resulting mixture was filtered to remove any residual starting material (4). Hexane (200 mL) was added to the filtrate and methylene chloride was removed by rotary evaporation under reduced pressure. Product crystallized from the hexane solution and was filtered to obtain (7) (95 g; 90%). HPLC analysis, 99.26% (purity, by peak area); 1H NMR (Bruker 400 MHz, CDCl3) δ 8.88 (s, 1H, Ar—H), 8.46 (s, 1H, Ar—H), 7.96 (m, 3H, Ar—H), 3.14 (s, 3H, —SO2CH3); mass spec. (electrospray), m/z 327 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]#[N:25])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCC#N)cc3=O)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (3.0 g), bromoacetonitrile (0.82 ml), potassium carbonate (4.42 g) and DMF (10 ml) was stirred at 80° C. for 2 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc). The resulting solid was washed with IPE to give the title compound (2.39 g) as a pale yellow solid.