Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[C:35]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=O)=O)([O-])=O.SCC(O)=O.O.[OH-].[Li+].C(OCC)(=O)C>CN(C)C=O>[C:43]1([C:35]2[N:34]([CH2:33][C:30]3[CH:29]=[CH:28][C:27]([CH2:26][NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=4)=[CH:32][CH:31]=3)[C:42]3[C:37]([CH:36]=2)=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)CCc1ccc(N(Cc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(NCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 66 %

Procedure:
To a solution of the residue obtained in Example 9 and mercaptoacetic acid (0.209 mL, 3.00 mmol) in N,N-dimethylformamide (2 mL) was added lithium hydroxide monohydrate (0.252 g, 6.00 mmol), and the mixture was stirred at room temperature for 64 hr. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (0.470 g, yield 66%, 2 steps) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([Cl:15])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)C=Cc1cncc(Br)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C=Cc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(5-Bromo-pyridin-3-yl)-acrylic acid (26.2 g, 114.7 mmol) prepared in Step 1 was added to thionyl chloride (100.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 3-(5-bromo-pyridin-3-yl)-acryloyl chloride as an unpurified dark brown liquid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](I)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COCCOC.[Cl:46][C:47]1[CH:56]=[C:55]2[C:50]([C:51](B3OC(C)(C)C(C)(C)O3)=[CH:52][CH:53]=[N:54]2)=[CH:49][CH:48]=1.[OH-].[Ba+2].[OH-].O>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>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:51]2[C:50]4[C:55](=[CH:56][C:47]([Cl:46])=[CH:48][CH:49]=4)[N:54]=[CH:53][CH:52]=2)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(I)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)OB(c2ccnc3cc(Cl)ccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(-c2ccnc4cc(Cl)ccc24)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl) silyl]oxy}methyl)cyclopentyl]oxy}-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (258.4 mg, 0.0003752 mol) in 1,2-Dimethoxyethane (3.0 mL, 0.029 mol) was added 7-chloroquinoline-4-boronic acid pinacol ester (0.158 g, 0.000546 mol), barium hydroxide (0.228 g, 0.00133 mol), water (0.5 mL, 0.03 mol) and Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol), and the mixture was heated at 90° C. overnight. The reaction was cooled, quenched by addition of water and the mixture was extracted with DCM (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 30% EtOAc/hexanes) to obtain 180 mg (66.2%) mg. Reference: Cammidge, A. N.; Crepy, K. V. L. Tetrahedron, 2004, 60, 4377-4386.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH3:20])=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:17][C:16]=2[C:27](N(OC)C)=[O:28])=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH2:33]1COC[CH2:34]1>>[CH3:20][C:19]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=2)=[C:16]([C:27](=[O:28])[CH2:33][CH3:34])[S:17][C:18]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CON(C)C(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: C1CCOC1
Product: CCC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C

Procedure:
To a stirred solution of 3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N,4-dimethyl-5-morpholinothiophene-2-carboxamide (compound 24f, 0.120 g, 0.25 mmol) in anhydrous THF (10 ml) at 25° C., Grignard reagent (ethyl magnesium bromide, 0.17 g, 1.25 ml, 1.25 mmol) was added dropwise and the reaction mixture was heated to 70-75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., reaction mixture was quenched by adding a saturated ammonium chloride solution (10 ml) and the resulting mixture was extracted with ethyl acetate (2×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent in the dried organic layer was evaporated under a reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40-45% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by precipitation by dissolving 0.056 g of this compound in ethyl acetate (1.0 ml) and precipitating it by the slow addition of diisopropyl ether. The precipitate was filtered to obtain the title compound. (0.047 g, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:71]([O:75][C:76](=[O:78])[NH2:77])([CH3:74])([CH3:73])[CH3:72]>O1CCOCC1.O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:77][C:76]([O:75][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:78])[N:17]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Reactant: CC(C)(C)OC(N)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1noc2cc(Oc3ccnc(NC(=O)OC(C)(C)C)n3)ccc12
Temperature: 110 °C
Reaction time: 4.5 h

Procedure:
A solution of 1.4 g (4.3 mMol) 6-(2-chloro-pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid ethyl ester (Step 4.1) in 32 ml dioxane is degassed repeatedly by evaporation and flushing with N2. Then 2.1 g (6.44 mMol) Cs2CO3, 77 mg (0.13 mMol) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 39.3 mg (0.0429 mMol) tris(dibenzylidenaceton)dipalladium(0) and 603 mg (5.15 mMol) carbamic acid tert-butyl ester are added successively. After 4.5 h stirring at 110° C., the mixture is cooled to rt and another 77 mg 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 39.7 mg tris(dibenzylidenaceton)dipalladium(0), 603 mg carbamic acid tert-butyl ester and 2.1 g Cs2CO3 are added and stirring is continued for 5 h. Then the cooled mixture is poured into EtOAc and water, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated together with 8 g SiO2. The resulting powder is put on top of a chromatography column (SiO2; CH2Cl2) and the title compound eluted with CH2Cl2→CH2Cl2/EtOAc 4:1: MS: [M+1]+=401; HPLC: tRet=15.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: Nc1ccccc1S
Solvent: CCO
Product: Nc1ccccc1SC(c1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 9.5 %

Procedure:
20 g of α-benzyloxycarbonylamino-β-phenylacrylic acid and 10 g of o-aminobenzenethiol were mixed with 40 ml of ethanol and the resulting mixture was heated under reflux for 20 hours. After cooling to room temperature, the precipitated crystalline component was separated by filtration and washed with ethanol to obtain 2.7 g of crystals. This product decomposed at 198° C.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].[Li+:12].[OH-:13]>O>[F:9][C:4]([F:10])([S:5]([OH:13])(=[O:7])=[O:6])[C:3]([O-:2])=[O:11].[Li+:12]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: O=C([O-])C(F)(F)S(=O)(=O)O
Temperature: 25 °C

Procedure:
In the first step, methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (56.6 g, 0.29 mol) was added dropwise to an aqueous solution of 23.1 g (0.96 mol) LiOH in 200 mL of water at 0° C. After completing the addition, the reaction mixture was warmed gradually to room temperature and then heated to reflux for 16 h. The mixture was cooled to room temperature and insoluble inorganic salts were removed by filtration. The filtrate was acidified by slow addition of 5N HCl to a pH of 1. Water was distilled off and the crude product was dried under reduced pressure to produce the product lithium difluorosulfoacetate as crude and white waxy solid.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:37])[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]([F:33])=[C:26]([O:34][CH2:35][CH3:36])[CH:25]=3)[CH2:19][CH2:18]2)[CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].O.Cl>C1COCC1.CO>[CH2:31]([O:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([O:34][CH2:35][CH3:36])[C:27]=1[F:33])[CH2:23][N:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[O:37])[CH2:22][CH2:21]1)[CH3:32]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3cc(OCC)c(F)c(OCC)c3)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(OC(C)(C)C(=O)O)c3)CC2)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.9 %

Procedure:
0.54 g (1.0 mmol) of 2-{3-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylcarbamoyl]-phenoxy}-2-methyl-propionic acid ethyl ester (example 50k) was reacted with 1.0 mL of LiOH/water (1.0 molar) in 15 mL of THF/MeOH (2:1) at 0° C. and subsequent temperature increase to rt. After 5 h, the reaction mixture was poured into crashed ice, the pH was adjusted to ˜7.0 with aq. HCl (1N) and the reaction mixture was extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of MeCl2/MeOH) to yield 0.135 g of the title compound as colorless solid. MS: 503.1 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9](Cl)([CH3:11])[CH3:10].NC(N)=[S:18].C(O)C.[OH-].[Na+]>CCOCC.O>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([SH:18])([CH3:11])[CH3:10]
Reactant: COC(CC(C)CCCC(C)(C)Cl)OC
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: COC(CC(C)CCCC(C)(C)S)OC

Procedure:
A mixture of 10 g. of 1,1-dimethoxy-7-chloro-3,7-dimethyloctane, one equivalent of thiourea and 100 ml. of 95% ethanol is refluxed for about 24 hours. Then a solution of 1.5 equivalents of sodium hydroxide in 50 ml. of water is added and the mixture refluxed for about 2 hours. After cooling to about room temperature, the solution is carefully acidified and ether is added. The organic layer is separated, washed with water, dried over calcium sulfate and evaporated to give 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane which is purified by distillation.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][OH:35])=[NH:33])=[CH:30][N:29]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:35][N:34]=[C:32]([C:31]4[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=4)[N:33]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.31) (188 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (22 mg, 9%). MS (ISP) 492.1 [(M+H)+]; mp 264° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[N:19][CH:18]=[N:17][CH:16]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(-c2cncnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyrimidin-5-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.075 mmol), β-alanine (672 mg, 7.54 mmol) and NaOMe solution (11 mL, 5.66 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4, and the resulting precipitate was isolated by filtration to give 17 mg of the title compound as a yellow solid. MS: (+) m/z 522.23 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:1]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[CH:2]3)=[CH:12][CH:13]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1cnc2nc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=C(Nc1ccc(-n2cnc3ncccc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from imidazo[4,5-b]pyridine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[C:26]([O:30][C:31]([N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=N[C:49]2C=CC=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:26]([O:30][C:31]([N:33]1[CH:37]=[CH:36][C:35]([N:38]([C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=3)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH2:48][CH3:49])=[N:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (100 mg, 0.24 mmol), 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (51 mg, 0.24 mmol), HATU (160 mg, 0.42 mmol), and TEA (0.13 mL) in DMF (1.5 mL) was stirred at room temperature overnight. It was purified with HPLC to give 3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-pyrazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:24]=1.C(O)(=O)C>C(O)C>[ClH:1].[C:13]([C@@:10]1([CH:15]2[CH2:17][CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:24]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: CNC(=O)Cn1cc(N)cn1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CNC(=O)Cn1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Product: Cl
Yield: 58.2 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (130 mg) obtained in Step E of Example 103, 2-(4-amino-1H-pyrazol-1-yl)-N-methylacetamide (84 mg) and acetic acid (31 μL) in ethanol (3.0 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the residue (190 mg) in ethanol (5.0 mL) was added 1 M hydrochloric acid (0.50 mL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (120 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>O.[Cu]Cl>[NH2:6][C:3]1[CH:4]=[CH:5][N:1]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:2]=1
Reactant: Brc1cccnc1
Reactant: Nc1cc[nH]n1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn(-c2cccnc2)n1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
A 4-neck round bottomed flask (500 mL) was charged with copper(I) chloride (2.51 g, 25.3 mmol), 1H-pyrazol-3-amine (15.8 g, 190 mmol), potassium carbonate (35.0 g, 253 mmol), and N,N-dimethylformamide (100 mL). The mixture was stirred under nitrogen for 10 minutes and 3-bromopyridine (12.2 mL, 127 mmol) was added. The mixture was heated at 110° C. for 18 hours, at which point HPLC analysis indicated that ˜15.5% 3-bromopyridine remained. The reaction was allowed to cool to 20° C. and concentrated to give a brown residue. Water (200 mL) was added and the resulting suspension was stirred at 20° C. for 2 hours and filtered. The solid was rinsed with water (2×50 mL) and dried to afford a pale green solid. The solid was suspended in water (200 mL) and the resulting suspension was heated at 90° C. for 2 hours and was filtered hot through a Celite® pad. The pad was rinsed with hot water (50 mL). The combined filtrates were allowed to cool to 20° C. to afford a yellow suspension, which was stirred at 20° C. for 2 hours and filtered. The solid was rinsed with water (2×50 mL) and air dried to afford the desired product as a light yellow crystalline solid (11.6 g, 57%): mp 169-172° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.07-8.82 (m, 1H), 8.33 (dd, J=4.6, 1.5 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 8.00 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.42 (ddd, J=8.5, 4.6, 0.8 Hz, 1H), 5.80 (d, J=2.6 Hz, 1H), 5.21 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 157.67, 144.68, 138.00, 136.22, 128.30, 123.95, 123.17, 97.08; ESIMS m/z 161 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].[CH2:31](I)[CH2:32][CH2:33][CH3:34]>>[CH2:31]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:28])[CH2:18][CH2:17]2)=[CH:20]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCI
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 0.119 g (0.31 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester, 0.022 g (0.53 mmol) of NaH in 60% of mineral oil and 0.044 mL (0.41 mmol) of butyl iodide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.054 g (42% of yield) of the desired product.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16](OC)=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:22][CH3:23].[C:24](=[O:27])(O)[O-].[Na+].Cl[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33].[I-].[K+]>C(O)C>[OH:21][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:27][CH3:24])[CH2:12][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:22][CH3:23])=[CH:2][CH:11]=2)[CH2:6][CH2:7][N:8]1[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(O)cc32)cc1O
Reactant: CC(C)=CCCl
Reactant: O=C([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CCN(CC=C(C)C)C2Cc1ccc(OC)c(O)c1

Procedure:
1.38 g. (4.37 mmol) (-)-7-Hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline in 25 ml. anhydrous ethanol is mixed with 0.9 g. (10.7 mmol) sodium bicarbonate, 0.44 g. (4.2 mmol) 1-chloro-3-methylbut-2-ene and 100 mg. potassium iodide. The reaction mixture is allowed to react for 1 hour at ambient temperature and for 4 hours at 80° C. The usual working up and chromatographic purification on silica gel with chloroform as elution agent gives (3-hydroxy-4-methoxybenzyl)-6-methoxy-2-(3-methylbut-2-enyl)-1,2,3,4-tetrahydroisoquinoline in the form of a yellowish foam.