Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH2:21](OB(C=C)OCCCC)[CH2:22]CC.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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:17]1([CH3:20])[CH:18]=[CH:19][C:14]([S:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([CH:21]=[CH2:22])[CH:3]=[C:4]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: C=CB(OCCCC)OCCCC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
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: COCCOC
Product: C=Cc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Yield: 84.8 %

Procedure:
5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, (300 mg, 0.85 mmol), vinylboronic acid dibutylester, (184 mg, 1.0 mmol), potassium carbonate, (420 mg, 3.0 mmol) and Pd(Ph3P)4 were combined in 3 mL DME and 1 mL water in a tube under nitrogen and heated in a microwave reactor to 130° C. for 10 min. The organic layer was then separated and evaporated. The residue was purified by silica chromatography (eluent: methylene chloride), affording 215 mg(85%) 1-(Toluene-4-sulfonyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine. MS ES+ 299.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)cc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl-4-(4-bromophenoxy)piperidine-1-carboxylate and 5-(methylsulfonyl)indoline (0.11 g, 35%); MS: 373 (M−100).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.CCOCC.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: [Pd]
Agent: C#C
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CCCO)cc2c1O
Reaction time: 0.42 h
Yield: 14 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 134 (231.0 mg) and Pd/C (10%, 46.2 mg) are dissolved in 40 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 26 psi and monitored with the OAMS for complete reduction of the acetylene. The reaction is complete in 25 min and filtered over celite to remove the palladium. The filtrate is condensed to obtain a solid. The solid is suspended in ether, filtered, and collected to yield 31.8 mg (14%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[CH3:25][C:26]([CH3:28])=O>C(O)(C(F)(F)F)=O>[CH3:25][C:26]1([CH3:28])[O:11][C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=2[C:6](=[O:8])[O:7]1
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)O)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc2c(c1)OC(C)(C)OC2=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 27 %

Procedure:
To a stirred suspension of 4-methylsalicylic acid (50 g, Aldrich) in TFA (320 mL) under nitrogen was added TFAA (105 mL) followed by dry acetone (60 mL). The reaction mixture was heated to 65° C. for 5 hours. At this time was added another portion of acetone (50 mL) and heating was continued for 15 hours. The solvent was removed under reduced pressure and the residue was taken up with Et2O (250 mL). The organic layer was washed with a 10% aqueous solution of NaHCO3 (2×100 mL), brine and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by chromatography (Pet Ether/EtOAc 98/2) to give 17 g (27%) of the titled compound as a liquid. TLC-Pet. Ether/EtOAc (9/1): Rf=0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])C2)(=[O:18])[CH3:17].N1CCCCC1>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]2[C:27]3[C:26](=[CH:22][CH:21]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[CH:28]=3)[NH:25][C:24]2=[O:29])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cccn1-c1cc(Cl)cc(Cl)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)C(c1cccn1-c1cc(Cl)cc(Cl)c1)C(=O)N2
Yield: 40 %

Procedure:
2.68 g (11 mmol) of 3-[N-(3,5-dichlorophenyl)pyrrole-2-carboxaldehyde are added to a solution of 2.12 g (11 mmol) of 5-acetylaminoindolin-2-one in 220 ml of ethanol containing 0.5 ml of piperidine. The reaction medium is heated under reflux for 3 hours. After cooling, the precipitate formed is drained, washed with twice 5 ml of ice-cold ethanol and dried under reduced pressure. 1.81 g (40%) of 3-[N-(3,5-dichlorophenyl)pyrrol-2-yl]-5-acetylaminoindolin-2-one are thus obtained in the form of a yellow solid whose characteristic is the following: melting point=267° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1.[Na+].[I-]>CC(C)=O>[Cl-:1].[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N+:12]=1[CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Nc1ncccc1O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Nc1c(O)ccc[n+]1Cc1ccc(Cl)nc1
Product: [Cl-]
Temperature: 25 °C
Yield: 194.2 %

Procedure:
A suspension of 2-chloro-5-chloromethyl-pyridine (1.0 g, 6.17 mmol), 2-amino-pyridin-3-ol (0.68 g, 6.17 mmol) and NaI (0.93 g, 6.17 mmol) in acetone (10 mL) was refluxed for 12 h. After cooling to room temperature, solids were removed by filtration and the filtrate was evaporated under reduced pressure. The residue was triturated with ethyl acetate to yield 1.63 g of crude 2-amino-1-(6-chloro-pyridin-3-ylmethyl)-3-hydroxy-pyridinium chloride wich was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[OH2:20].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g, 0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 31/2 hrs. Then, under nitrogen atmosphere, dipropylamine (2.43 g, 0.024 mole) was added at room temperature and the reaction mixture was heated at reflux for 6 hrs. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was treated with water and refrigerated. The solid was collected by filtration, washed with water, and dried under high vacuum at 50°-60° C. overnight. The solid was recrystallized from isopropyl alcohol-water, collected, washed with water, and dried under high vacuum at 50°-60° C. overnight. Two crops gave 1.9 g (43%) of crystals, mp 122°-123° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([N:13]1[CH2:17][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][C:14]1=[O:26])[CH2:5][CH:6]1[CH:10]2[CH2:11][CH2:12][CH:7]1[CH2:8][CH2:9]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:7]12[CH:6]([CH2:5][CH:4]([N:13]3[CH2:17][C:16]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:15][C:14]3=[O:26])[C:3]([OH:27])=[O:2])[CH:10]([CH2:9][CH2:8]1)[CH2:11][CH2:12]2
Reactant: COC(=O)C(CC1C2CCC1CC2)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1C2CCC1CC2)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
In a flask was placed 3-bicyclo[2.2.1]hept-7-yl-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (35 mg, 0.089 mmol) in tetrahydrofuran (2 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (8 mg, 0.18 mmol) in water (2 mL) and stirred for 1.5 h at 25° C. The mixture was treated with a 1N aqueous hydrochloric acid solution to pH=2 and was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-bicyclo[2.2.1]hept-7-yl-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (32 mg, 97%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16]C(C#N)=[C:12]([CH:18]=O)[N:11]=1.[NH2:20][NH2:21].[CH3:22][CH2:23][OH:24]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][C:22]2[C:12]([N:11]=1)=[CH:18][N:21]=[N:20][C:23]=2[OH:24]
Reactant: CCO
Reactant: NN
Reactant: N#Cc1ccc(Nc2ccc(F)cc2F)nc1C=O
Product: Oc1nncc2nc(Nc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the product of step 3 in 3.0 mL of EtOH at 0° C. was added anhydrous hydrazine (0.16 mL, 5.1 mol). The ice bath was removed, and the homogeneous solution was stirred at RT for 15 min, then the EtOH was removed by rotovap. To the remaining mixture at RT was added 2.0 mL of glacial acetic acid, and the mixture stirred at RT for 5 min, then in an oil bath at 95° C. for 10 min. It was cooled to RT, and treated with 3 mL of water. The precipitated yellow solid was filtered, rinsed with 2×1 mL of water followed by 2×1 mL of ether. The solid was dried in a vacuum oven at 45° C. for 18 h, to afford 2-(2,4-difluorophenylamino)pyrido[3,2-d]pyridazin-5-ol as a yellow crystalline solid. MS (ESI, pos.ion) m/z: M+1=275.1
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[C:19]2[C:28](=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:30][C:18]=2[C:17]=1[F:39])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[C:19]2[C:28](=[O:38])[NH:29][CH2:30][C:18]=2[C:17]=1[F:39]
Reactant: Cc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)sn1
Temperature: 60 °C

Procedure:
To a stirred solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (82 mg, 0.146 mmol) in MeOH (2.0 mL) was added 4N HCl/dioxane (2.0 mL, 8.00 mmol). The reaction mixture was heated to 60° C. for 1 hour. Following reaction, the mixture was concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to yield crude desired compound as a yellow solid. The crude product was recrystallized from MeOH-Et2O to give a hydrochloride salt of the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37-1.56 (m, 2H), 1.58-1.83 (m, 4H), 1.84-2.04 (m, 2H), 2.46 (s, 3H), 3.73 (br. s., 1H), 4.17-4.29 (m, 1H), 4.47 (s, 2H), 7.17 (d, J=5.37 Hz, 1H), 7.84 (br. s., 3H), 8.66 (s, 1H), 8.76 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H20FN5OS, 362. found, 362.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-methoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example A7) (5.79 g, 17.2 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a yellow solid (5.36 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][CH:8]1[O:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][N:6]([CH2:7][CH:8]1[O:13][CH2:12][CH2:11][CH2:10][O:9]1)[C:31](=[O:32])[CH2:30][Cl:29])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(CNCC1OCCCO1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCCO1)C(=O)CCl)OCC

Procedure:
N-(2,2-Diethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-amine (4 grams), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of 5° to 10° C and chloroacetyl chloride (1.5 ml) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture reaches room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1N)(=[O:5])=[O:4].[N:15]([O-])=O.[Na+].[S:19](=[O:21])=[O:20]>Cl.C(O)(=O)C.O>[CH3:1][N:2]([CH3:14])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:19]([NH2:15])(=[O:21])=[O:20])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cc1ccccc1N
Reactant: O=N[O-]
Reactant: O=S=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)Cc1ccccc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 53.5 g of the product of Example 3 in a mixture of 225 ml of concentrated hydrochloric acid and 75 ml of glacial acetic acid was added a solution of 21.4 g of sodium nitrite in 70 ml of water at -5° to 0°. The solution was stirred at 0° for 15 minutes, then poured into a mixture of 6 g of cuprous chloride, 48 ml of liquid sulfur dioxide in 300 ml of glacial acetic acid at 0°-4°. This mixture was stirred at 0° for 1 hour, then at 25° for 2 hours before being poured into 2 liters of ice-water. The precipitate was filtered and washed with water then suspended in 250 ml of ether and treated with 11.0 ml of liquid anhydrous ammonia at 5°-15°. After stirring at 25° for 30 minutes the precipitate was filtered off and washed well with ether then water. Oven drying at 60° gave 40.2 g of 2-[(dimethylamino)sulfonylmethyl]benzenesulfonamide, m.p. 145°-150°.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1.C(O)C(N)(CO)CO>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:13]=2)[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(c1ccc(NCc2ccc(Cl)cc2)cc1)N1CCN(c2ccccc2)CC1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)cc1)N1CCN(c2ccccc2)CC1
Reaction time: 18 h
Yield: 125.6 %

Procedure:
To a stirred solution of [4-(4-chloro-benzylamino)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone (30 mg, 0.07 mmol) and phenylsulfonyl chloride (14.2 μl, 0.11 mmol) in anhydrous dichloromethane (1 ml) was added pyridine (7.2 μl, 0.09 mmol) and the reaction was stirred at ambient for 18 hours. PS-trisamine (32 mg, 0.13 mmol) was added and the mixture was agitated for 3 hours then filtered. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid (48 mg, 98% yield). HPLC retention time 7.7 min. Mass spectrum (ES+) m/z 547 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-chlorolactic acid (5.0 g, 40 mmol) and 4-chlorophenol (9.3 g, 72 mmol) in 40 ml 3.3 N sodium hydroxide is stirred under reflux for 2 hours. Subsequently the reaction mixture is cooled to room temperature and acidified to pH 3 with concentrated hydrochloric acid. The resulting white crystals are filtered and dissolved in hot water. This hot solution is adjusted to pH 1 with concentrated sulfuric acid. Upon cooling, 3-(4-chloro-phenoxy)-2-hydroxy-propionic acid is collected as clear crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: NCCc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl]imidazole (1.04 g, 4 mmol) and 2-(3-chlorophenyl)ethylamine (0.63 g, 4 retool) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.88 g (63%) of the title product:
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28](=[O:36])[N:29]([CH3:35])[C@H:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)[CH2:11]2)=CC=1.[N+:39]([C:42]1[CH:54]=[CH:53][C:45]([CH2:46][O:47][C:48]([NH:50][CH:51]=N)=[O:49])=[CH:44][CH:43]=1)([O-:41])=[O:40]>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([C:28](=[O:36])[N:29]([CH3:35])[C@H:30]2[CH2:34][CH2:33][N:32]([CH:51]=[N:50][C:48]([O:47][CH2:46][C:45]3[CH:53]=[CH:54][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=3)=[O:49])[CH2:31]2)[CH2:11]1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Product: CN(C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCN(C=NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 57 %

Procedure:
Following a procedure similar to that described in Preparations 23(iii) and 23(iv), but using 1.00 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-[N-methyl-N-[(3S)-pyrrolidin-3-yl]carbamoyl]pyrrolidine hydrochloride and 405 mg of N-(4-nitrobenzyloxycarbonyl)formamidine, 620 mg of the title compound were obtained as a powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][OH:40]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:37][CH2:38][CH2:39][OH:40])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol (compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (42 mg) and 3-bromo-1-propanol (0.03 ml) were added to the supension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (32 mg, yield 68%).
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO.O>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:8]2([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[NH:19]1
Reactant: O=C(C(=O)c1ccccn1)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccn2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 1 -phenyl-2-(2-pyridinyl)ethanedione (800 mg, 3.79 mmol) and 2-guanidinobenzimidazole (560 mg, 3.15 mmol) in methanol (20 mL) was treated with a solution of sodium hydroxide (40 mg, 1.0 mmol) in 1 mL of water. The title compound was isolated as pale yellow crystals (160 mg, 20% yield). 1H NMR (300 z, d6 -DMSO) δ 12.0 (br. s, NH, 1H) 11.5 (br s, NH, 2 H), 10.0 (br s, NH, I H), 8.6 br s, NH, 1 H), 8A1 (m, 2 H), 7.55 (t, J=6.9 Hz, 2 H), 7.30-7.10 (m, 8 H), 6.98 (dd, J=6.0, 3.1 Hz, 4 H); MS (ESI) m/z 526 [M+H+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1C(=O)OCc1ccccc1

Procedure:
A solution of 4.3 g (S)-2-Methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester in 20 ml dichloromethane was stirred in the presence of 10 ml TFA for 16 h. The solution was concentrated and the residue codistilled twice with toluene to give the crude hydrotrifluoroacetate. Yield: 6.4 g.