Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(OC)cc2)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-methoxy-phenyl)-methanone (Example 358) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4-methoxy-phenyl)-methanone. MS (M+H)+, 406
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1ncccc1O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1ncccc1O

Procedure:
3-Hydroxy-picolinic acid (15.6 g, 42.1 mmol), ethanol (360 mL), benzene (100 mL) and 98% sulfuric acid (6 mL) were heated under reflux for 40 h. After evaporation of the ethanol and benzene, the residue was dissolved in water, neutralized with sodium bicarbonate, and extracted with chloroform. The organic layer was dried (MgSO4), filtered, and then the solvent was evaporated to give ethyl 3-hydroxy-picolinate as a brown oily residue (11.0 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:12][OH:13])([CH2:8][N:9]=[N+:10]=[N-:11])[CH2:4][N:5]=[N+:6]=[N-:7].S(=O)(=O)(O)O.[OH-].[Ca+2].[OH-].[CH3:22][C:23]([CH3:25])=O>>[N:5]([CH2:4][C:3]1([CH2:8][N:9]=[N+:10]=[N-:11])[CH2:12][O:13][C:23]([CH3:25])([CH3:22])[O:1][CH2:2]1)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NCC(CO)(CO)CN=[N+]=[N-]
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: CC1(C)OCC(CN=[N+]=[N-])(CN=[N+]=[N-])CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 mole of compound 1 was dissolved in 500 ml of dry acetone. After addition of 10 ml of concentrated sulfuric acid, the reaction mixture was stirred at room temperature for 2 hours. It was neutralized with calcium hydroxide and filtered and the filtrate and was concentrated to a syrup in vacuo. The crude product was further purified by column chromatography (eluting agent: chloroform/ethyl acetate 9:1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[O:8][CH:9]([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23](C(O)=O)[C:24]([OH:26])=[O:25])[C:20]#[C:21][CH3:22])=[CH:15][CH:14]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[O:8][CH:9]([CH3:30])[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([C:20]#[C:21][CH3:22])[CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:18]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CC(c1ccc(NC(=O)C(C)Oc2cccc(C(C)(C)C)c2)cc1)C(C(=O)O)C(=O)O
Solvent: C1COCCO1
Product: CC#CC(CC(=O)O)c1ccc(NC(=O)C(C)Oc2cccc(C(C)(C)C)c2)cc1
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
A solution of 304 mg (0.67 mmol) of 2-(1-{4-[2-(3-tert-butylphenoxy)propionylamino]-phenyl}but-2-ynyl)malonic acid in 10 ml of dioxane was boiled at 120° C. for 27 h. The reaction mixture was concentrated and separated by means of preparative HPLC (Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H2O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes 10% B→80% B; in 5 minutes 80% B→90% B). The product fractions were freeze-dried to obtain 214 mg (78%) of 3-{4-[2-(3-tert-butylphenoxy)propionylamino]phenyl}hex-4-ynoic acid. C25H29NO4 (407.51), LCMS (ESI-pos): 408 (M+H+).
Reaction SMILES: [C:1]1([C:13](Cl)=[O:14])[CH:6]=[C:5]([C:7](Cl)=[O:8])[CH:4]=[C:3](C(Cl)=O)[CH:2]=1.C1(N)C=CC=C(N)C=1.NC1C=CC=CC=1.C[CH:32]([OH:35])CN>CN1C(=O)CCC1.O>[C:13](=[C:1]1[CH2:2][CH:3]=[CH:4][C:5](=[C:7]=[O:8])[C:6]1=[C:32]=[O:35])=[O:14]
Reactant: CC(O)CN
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: Nc1cccc(N)c1
Solvent: O
Solvent: Nc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C=C1C=CCC(=C=O)C1=C=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, a 300 mL four-neck flask was charged with 30 g (0.113 mol) of 1,3,5-benzenetricarbonyl trichloride (Tokyo Chemical Industry) and 133.3 g of N-methyl-2-pyrrolidone (abbreviated below as “NMP”; Junsei Chemical Co., Ltd.), following which a solution of 9.16 g (84.8 mmol) of 1,3-phenylenediamine (DuPont K.K.) and 7.89 g (84.8 mmol) of aniline (Junsei Chemical Co., Ltd.) dissolved in 133.3 g of NMP (Junsei Chemical Co., Ltd.) was added dropwise over a period of 30 minutes at an internal temperature of 0 to 5° C. Following the completion of dropwise addition, the flask contents were stirred for 30 minutes at a temperature of 10° C. or below. A solution of 12.73 g (169.5 mmol) of DL-1-amino-2-propanol (Tokyo Chemical Industry) dissolved in 90 g of NMP (Junsei Chemical Co., Ltd.) was added dropwise to this at an internal temperature of from −3 to −1° C. over a period of 30 minutes, following which the temperature was raised to 70° C. and stirring was carried out for 2 hours. The reaction mixture was added to 3,000 g of pure water to effect re-precipitation and the resulting precipitate was collected by filtration, then dried at 150° C. for 3 hours in a vacuum desiccator. The resulting moist product was again dissolved in 180 g of N,N-dimethylacetamide (abbreviated below as “DMAc”) and stirred at 55° C. for 1 hour. Next, the DMAc solution was allowed to cool to 30° C., then added to 600 g of pure water heated to 50° C. and re-precipitated, followed by stirring at 50° C. for 1 hour. After allowing the contents to cool to 30° C., filtration was carried out and the filtrate was dried in a vacuum desiccator at 150° C. for 10 hours, giving 35.85 g of the target tricarbonylbenzene-based hyperbranched polymer (abbreviated below as “HPmDAP”). FIG. 1 shows the 1H-NMR spectrum obtained for HPmDAP.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:13])[N:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][C:12]1[N:11]=[N:10][C:9]([NH2:13])=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nncc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Product: Nc1nnc(Br)c(-c2ccccc2)n1
Yield: 64.1 %

Procedure:
6-Bromo-5-phenyl-1,2,4-triazin-3-amine (1.40 g, 64%) was prepared from 5-phenyl-1,2,4-triazin-3-amine (1.50 g, 8.70 mmol) and N-bromosuccinimide (4.50 g, 26.6 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:24]#[N:25]>>[C:24]([CH:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28])#[N:25]
Reactant: CC(C)CC(N)C#N
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)CC(C#N)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-4-methylpentanenitrile hydrochloride (CAN 72177-82-3) as starting materials. MS (EI): m/e=379.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[CH3:18][C:19](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:19]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:20])[CH3:18]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anyhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118° C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21](O)=[O:22])[CH:14]=[N:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:50])[C:30]=1[CH:31]([O:42][Si:43]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:44][CH3:45])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:50])[C:30]=1[CH:31]([O:42][Si:43]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:44][CH3:45])[CH2:32][N:33]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:21]([C:15]1[CH:14]=[N:13][N:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[C:16]=1[C:17]([F:18])([F:20])[F:19])=[O:22]
Reactant: CC[Si](CC)(CC)OC(CNCc1ccc(F)cc1)c1c(Cl)cncc1Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3ccc(F)cc3)CC(O[Si](CC)(CC)CC)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of acid D1 (6.22 g, 18.6 mmol) and amine A1 (8.67 g, 20.4 mmol) in DMF (100 mL) were added HATU (8.48 g, 22.3 mmol) and DIPEA (4.74 mL, 27.9 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford compound 1-1 (15 g, crude) as a brown gum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[O:12]1[C:16]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)=[CH:15][N:14]=[CH:13]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N>CS(C)=O.O.C(O)C>[Br:11][C:5]1[CH:6]=[C:7]2[N:8]=[C:21]([C:20]3[CH:19]=[CH:18][C:17]([C:16]4[O:12][CH:13]=[N:14][CH:15]=4)=[CH:24][CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(-c2cnco2)cc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(-c4cnco4)cc3)nc2c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
2-Amino-5-bromo-3-nitropyridine (218 mg) and 4-(1,3-oxazol-5-yl)benzaldehyde (173 mg) were suspended in dimethylsulfoxide (2 mL), followed by stirring at 80° C. for 20 minutes. Ethanol (4 mL) and 1M aqueous sodium hydrosulfite solution (3 mL) were added to the solution, followed by refluxing under heating for 15 hours. After the reaction mixture had been left to cool, water (20 mL) and concentrated aqueous ammonia solution (500 μL) were added thereto, and the precipitated solid was recovered through filtration, followed by washing with water and drying under reduced pressure, to thereby yield a 1:1 mixture (258 mg) of 5-[4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenyl]-1,3-oxazole and 5-[4-(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)phenyl]-1,3-oxazole.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[CH2:20]([Li])[CH3:21]>C1COCC1.C1CCCCC1.C1C=CC=CC=1>[CH2:20]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:21]
Reactant: [Li]CC
Reactant: COc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Solvent: C1CCCCC1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.0 g (38 mmol) [1-(2,6-dimethoxy-phenyl)-meth-(E)-ylidene]-(1-isopropyl-2-methyl-propyl)-amine in 30 ml dry THF cooled to −20° C. were added 91.2 ml of a 0.5M solution of ethyl lithium in cyclohexane/benzene drop-wise to keep temperature below 0° C. Then the mixture was stirred at −20° C. for further 30 min and the reaction quenched by addition of water. The aqueous phase was extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Purification of the crude product by flash chromatography on silica gel with a heptane/ethyl acetate gradient provided 4.30 g (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine as colourless liquid: MS (EI): 261.4 (M+.), 218.3 ((M-((CH3)2CH)+.), 100%).
Reaction SMILES: CO[C:3]([P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[O:4].Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15]>O1CCCC1>[NH2:17][C:14](=[N:16][C:3]([P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[O:4])[CH3:15]
Reactant: CC(=N)N
Reactant: CCOP(=O)(OCC)C(=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(=O)N=C(C)N

Procedure:
A solution of 98 parts of diethyl methoxycarbonylphosphonate plus 47 parts of acetamidine hydrochloride in 1000 parts of anhydrous tetrahydrofuran can be refluxed for 8 hours and the solvent then removed under reduced pressure to give diethyl 1-amino-1-methylmethyleneaminocarbonylphosphonate. In a similar manner, starting with the appropriate alkoxycarbonylphosphonate and imino compounds, the following compounds can be prepared:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:33][CH2:34][C:35]5[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 66.3 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-(aminomethyl)pyridine (available from Aldrich Chemical Company, Inc.; 67 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(pyridin-4-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (78 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 9.25 (t, J=5.8 Hz, 1H), 8.60 (d, J=6.0 Hz, 2H), 8.47 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.46-7.55 (m, 4H), 4.60 (d, J=5.8 Hz, 7H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].[C:13](OCC)(OCC)(OCC)[CH3:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:13]([CH3:14])=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(C(=O)NN)cc1I
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: Cc1nnc(-c2ccc(C)c(I)c2)o1
Temperature: 150 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A stirred mixture of 3-iodo-4-methylbenzohydrazide (preparation 55b, 5.00 g, 18.1 mmol) and triethyl orthoacetate (11.00 mL, 58.2 mmol) in acetic acid (30 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled and concentrated in vacuo. Aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with dichloromethane. The organic solution was dried (MgSO4) and the solvent was removed in vacuo. The crude material was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (4.26 g, 78%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([NH:23][C:24]#[N:25])[CH:20]=[C:19]([CH3:26])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:22]=[C:21]([NH:23][C:24]2[NH:29][N:28]=[N:27][N:25]=2)[CH:20]=[C:19]([CH3:26])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:16][CH2:17]2)(=[O:12])=[O:13])[CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(NC#N)cc(Cl)c1Oc1ccc(O)c(S(=O)(=O)NC2CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(Nc2nnn[nH]2)cc(Cl)c1Oc1ccc(O)c(S(=O)(=O)NC2CC2)c1
Temperature: 165 °C

Procedure:
5-[2-Chloro-6-methyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-N-cyclopropyl-2-hydroxy-benzenesulfon-amide was prepared from 5-[2-chloro-4-cyanoamino-6-methyl-phenoxy]-N-cyclopropyl-2-hydroxy-benzenesulfonamide according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (1.2 equiv) and ammonium chloride (10 equiv) were used, and the reaction was heated to 165° C. for 3 hours. After the reaction had been acidified, the aqueous mixture was washed with ethyl acetate (3×10 ml). The combined organic extracts were extracted with aqueous 1N HCl (3×50 ml), and brine (50 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane 25:3:72) to afford the title product of Example 5. MS (APCI+) Calc.: 436.1, Found: 436.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([NH:24]C(OCC2C=CC=CC=2)=O)[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([NH2:24])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(N)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 103.1 %

Procedure:
4-[2-(2-Benzyloxycarbonylamino-propoxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (5.7 g, 12.15 mmol) and 10% wet palladium on carbon (5.0 g) were dissolved in methanol (200 mL) at r.t. The solution was stirred under hydrogen for about 4 hours. The mixture was filtered through a bed of celite. The solvent was removed under reduced pressure to afford the title compound as a colorless oil (4.2 g, 100%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])([CH3:20])[CH2:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1)[CH3:8].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[CH:26][CH:25]=1>CN(C=O)C>[C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:16]2[C:17]3[C:12](=[CH:11][CH:10]=[C:9]([CH2:7][CH3:8])[CH:18]=3)[C:13]([CH3:20])([CH3:21])[CH2:14][C:15]2=[O:19])=[CH:29][CH:28]=1)#[N:37]
Reactant: CCc1ccc2c(c1)NC(=O)CC2(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CC2(C)C
Reaction time: 0.75 h

Procedure:
12.5 g of potassium tert-butoxide are added at 20° to a solution of 20.3g or 7-ethyl-1,2,3,4-tetrahydro-4,4-dimethyl-2-oxoquinoline [mip. 120°; obtainable by reaction of m-ethylaniline with 3,3-dimethylacryloyl chloride in toluene/methylene chloride to give N-(3,3-dimethylacryloyl)-m-ethylaniline (m.p. 90°) and cyclisation with AlCl3 at 60°-100°]in 700 ml of DMF. The mixure is stirred for 45 minutes, a solution of 30.5g of 4-bromomethyl-2'-cyanobiphenyl in 300 ml of DMF is then added dropwise and the mixture is stirred overnight, evaporated and worked up in conventional manner to give 1-(2'-cyanobiphenyl-4-ylmethyl)-7-ethyl-1,2,3,4-tetrahydro-4,4-dimethyl-2-oxoquinol ine, m.p. 171°-172°.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22](O)[CH2:21][CH2:20][CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19]2
Reactant: OC1CCCc2cc(Cl)ccc21
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OC2CCCc3cc(Cl)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 6-chloro-1,2,3,4-tetrahydronaphthalen-1-ol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C19H15ClN4O, 351; Found, 351.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17])(=O)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17]
Reactant: COc1c(OC(C)=O)ccc(C=O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 4-formyl-2-methoxy-3-nitrophenyl acetate 4.54 g (19.0 mmol) and potassium carbonate 5.24 g (37.9 mmol) in methanol 40m was stirred at room temperature for 2 hours. The reaction mixture was poured into water, acidified by 1N HCl solution and extracted into AcOEt. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed with n-hexane to give the title compound 3.60 g as white solid. Yield 96.3%.
Reaction SMILES: COC1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2SC=C(C(O)=O)N=2)CC1)=O.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[C:35]2[C:41]([NH:43][CH2:44][CH:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[O:56][C:55]([C:57]([O:59]CC)=[O:58])=[CH:54][CH:53]=2)[CH2:47][CH2:46]1)=[O:42]>CCO>[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[C:35]2[C:41]([NH:43][CH2:44][CH:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[O:56][C:55]([C:57]([OH:59])=[O:58])=[CH:54][CH:53]=2)[CH2:47][CH2:46]1)=[O:42]
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Agent: COc1ccc2[nH]nc(C(=O)NCC3CCN(Cc4nc(C(=O)O)cs4)CC3)c2c1
Solvent: CCO
Product: O=C(O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1

Procedure:
5-{[4-({[(5-Bromo-1H-indazol-3-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}furan-2-carboxylic acid 22 was prepared, according to the procedure described for compound 8, starting from compound 15 and using EtOH as solvent. Yield: 264 mg, 98%.