Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: COc1ccc(N)cn1
Agent: [Cu]I
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
A mixture of 2,4-dichloro-5-iodopyrimidine (274 mg, 0.997 mmol), 5-amino-2-methoxypyridine (0.247 mL, 1.994 mmol), N,N-diisopropylethylamine (0.347 mL, 1.994 mmol) and copper(I) iodide (38 mg, 0.199 mmol) in dioxane (2 mL) was stirred at 100° C. for 3 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange oil. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (242 mg, 0.667 mmol, 67.0% yield). 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H); 8.28 (d, J=1.90 Hz, 1H); 7.83 (dd, J=8.84, 2.56 Hz, 1H); 7.01 (s, 1H); 6.81 (d, J=8.77 Hz, 1H); 3.96 (s, 3H). m/z (ESI, +ve ion) 362.9 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:28]([OH:30])=O)=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[C:28](=[O:30])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:19][C:20]([CH3:26])([CH3:25])[C:21]([CH3:23])([CH3:24])[O:22]4)[C:13]=3[CH3:27])[CH2:10][C:8]=2[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(NCc2nc(C(C)(C)C)sc2C(=O)O)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a mixture of 2-tert-butyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)methyl)thiazole-5-carboxylic acid 109e (430.37 mg, 0.0010000 mol) in methylene chloride (10 mL) was added N,N-diisopropylethylamine (870.91 uL, 5.0 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (1.1407 g, 0.0030000 mol). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with water. The organic layer was separated, and dried with anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified on silica eluted with a gradient of 0 to 20% Ethyl acetate in Heptane to afford 2-tert-butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 109f (163 mg, 40%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([O:21][CH3:22])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:32][C:30]1[CH:31]=[C:24]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[O:21][CH3:22])[C:25]([C:26]#[N:27])=[CH:28][CH:29]=1
Reactant: N#Cc1ccc(Cl)cc1Br
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21, 542 mg, 1.66 mmol) in dioxane (10 mL) and water (2 mL) was added 2-bromo-4-chlorobenzonitrile (300 mg, 1.38 mmol), and sodium carbonate (441 mg, 4.16 mmol). The reaction was degassed and then tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.14 mmol) was added and the reaction mixture further degassed. The reaction was on a preheated hot plate (110° C.) for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:cyclohexane 1:1 to give the title compound as a dark solid in 62% yield, 0.345 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH3:42])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.296 mmol, 0.16 g; Example 43) in DMF (2 mL) at 0° C. was added sodium hydride (80 mg) followed by methyl iodide (0.2 mL) and continued stirring at 0° C. for 30 min. The reaction mixture was diluted with ethyl acetate (10 mL) and quenched excess NaH by drop-wise addition of methanol. This was washed with brine (10 mL), organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluating with 20% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.145 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC)CCCc1cccc(-c2ccc(CN)cc2)n1
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCc1cccc(-c2ccc(CNCc3ncc[nH]3)cc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.1 %

Procedure:
An anhydrous methanol solution (0.50 ml) containing the compound (30.1 mg) obtained in Example 36-5 and 2-imidazole carboxaldehyde (10.1 mg) was added with trimethyl orthoformate (0.029 ml), and the whole was stirred at room temperature for 14 hours. Sodium borohydride (17.0 mg) was added thereto and the whole was stirred for 30 minutes. The solvent was distilled off. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining the subject compound (30.4 mg).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][C:11]([CH3:13])=[O:12]>>[C:11]([C:13]1[CH:8]=[CH:9][CH:4]=[CH:5][C:6]=1[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:5]=1)(=[O:12])[CH3:10]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccccc1-c1cccc(-c2ccccc2)c1

Procedure:
Nitrobenzene is stripped with steam and the solid residue is dissolved into acetone. After filtration and the acetone evaporation, 400 g of crude product is obtained.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O.C(N(CC)C=O)C>CN(C)C=O>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ccnc2ccccc12
Agent: CCN(C=O)CC
Solvent: CN(C)C=O
Product: Clc1ccnc2ccccc12

Procedure:
reacting the 4-hydroxyquinoline of formula (11) with thionyl chloride in the presence N,N-dimethylformamide or N,N-diethylformamide to obtain a 4-chloroquinoline of formula (12), ##STR11##
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].[OH-].[K+]>C1COCC1.O>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
Boc-Gly-Pro-Nleu-OEt (4.3 g, 0.0104 mol.) was dissolved in 80 ml THF/H2O (v/v, 1:1) and the solution was chilled to 0° C. on a water-ice bath. KOH (1.1 g dissolved in 20 ml H2O) was added while stirring the solution. After a while, the bath was removed and the stirring was continued for one more hour. The THF was removed under reduced pressure. The aqueous solution was extracted by ethyl acetate 2×50 ml. Then, the aqueous layer was chilled to 0° C. and was acidified to about pH=3 by addition of concentrated HCl while swirling the solution vigorously at the same time (the aqueous layer was covered by 50 ml ethyl acetate). The product was extracted from the aqueous layer by ethyl acetate 3×50 ml. The organic layer was combined and dried by Na2SO4. The ethyl acetate was removed under reduced pressure. Column chromatography (E/H:5:2) was carried out to obtain the pure product (white solid, 3.6 g, 92%). TLC Rf=0.44 (developing solvents: CMA, 85:15:3). FAB-MS, observed (M+H)+ =386. Analytical RP-HPLC chromatogram, single peak, retention time RT=13 min. (25-60% B in 30 min.). 1H-NMR (500 MHz, DMSO-d6, 25° C., assignment by TOCSY) δ 12.50 (s, 1H, carboxyl), 6.62 (m, 1H, Gly-NH), 4.92 (d, Pro-α), 4.72 (d, Pro-α), 4.56 (d, Nleu-α), 4.48 (d, Pro-α), 4.12 (m, Nleu-α), 4.00-3.90 (m, Nleu-α), 3.83-3.66 (m, Nleu-α, Gly-α), 3.64-3.50 (m, Gly-α, Nleu-α), 3.50-3.33 (m, Pro-δ), 2.34-1.60 (sets of bands, Pro-β, Pro-γ, Nleu-γ), 1.38 (s, 9H, Boc-CH3), 0.88 (dd, Nleu-δ), 0.75 (dd, Nleu-δ).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[CH:3]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Br)cs2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(-c3ccc(N)nc3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiophen-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.88) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.122 g, 0.55 mmol) according to the general procedure VI. Obtained as a white solid (0.115 g, 55%). MS (ISP) 412.2 [(M+H)+]; mp 175° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([CH:18]=O)[S:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:25](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18]#[N:25])[S:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C=O)cc21
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C#N)cc21

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1c) using 4-{[t-butyl(dimethyl)silyl]oxy}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxaldehyde (4.4 g, 15.3 mmol) that was obtained in Example 8 (8c), hydroxylamine hydrochloride (1.1 g, 16 mmol), triethylamine (4.1 ml, 30 mmol), and N,N′-dicyclohexylcarbodiimide (3.4 g, 16 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (4.1 g) in a yield of 94% as a colourless oily product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:15]=[C:14]2[C:8]([C:9](=[O:19])[CH2:10][CH2:11][N:12]([CH3:18])[S:13]2(=[O:17])=[O:16])=[CH:7]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:15]=[C:14]3[C:8]([C:9](=[O:19])[CH2:10][CH2:11][N:12]([CH3:18])[S:13]3(=[O:17])=[O:16])=[CH:7]2)[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN1CCC(=O)c2cn(CCCCCl)cc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCn2cc3c(c2)S(=O)(=O)N(C)CCC3=O)CC1
Yield: 69.5 %

Procedure:
A suspension of 152 mg (0.5 mmol) of Compound 19, 144 mg (0.75 mmol) of 1-(2-methoxyphenyl)piperazine, 104 mg (0.75 mmol) of potassium carbonate and 150 mg (1 mmol) of sodium iodide in 20 ml of acetonitrile was refluxed for 17 hours. Post-treatment was conducted in a similar manner as in Example 18. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=1/19), whereby 160 mg of the title compound were obtained (yield: 99%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:12]([C:11]4[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[CH:9][CH:10]=4)=[O:13])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: O=C(Cl)c1ccnn1-c1ccccc1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Product: O=C1Cc2ccc(C(=O)c3cccc(NC(=O)c4ccnn4-c4ccccc4)c3)cc2N1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A dry flask was charged with 2-Phenyl-2H-pyrazole-3-carbonyl chloride (0.164 g, 0.794 mmol) and THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 2-Phenyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.255 g, 0.600 mmol, 76%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=2)[C:16]([OH:18])=O)=[N:4][NH:5][C:6](=[O:9])[C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([O:54][CH:55]([O:63][CH2:64][CH3:65])[CH2:56][NH:57][CH2:58][C:59]([O:61][CH3:62])=[O:60])[CH3:53]>CN(C=O)C.CCOC(C)=O>[CH2:64]([O:63][CH:55]([O:54][CH2:52][CH3:53])[CH2:56][N:57]([C:16](=[O:18])[C:15]1[CH:19]=[C:11]([CH2:10][C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[C:6](=[O:9])[NH:5][N:4]=2)[CH:12]=[CH:13][C:14]=1[F:20])[CH2:58][C:59]([O:61][CH3:62])=[O:60])[CH3:65]
Reactant: Cc1c(Cc2ccc(F)c(C(=O)O)c2)n[nH]c(=O)c1C
Reactant: CCOC(CNCC(=O)OC)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(CN(CC(=O)OC)C(=O)c1cc(Cc2n[nH]c(=O)c(C)c2C)ccc1F)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoic acid (Preparative Example 2) (1 eq), TBTU (1.2 eq), and DIPEA (1.5 eq) in DMF (0.18M) was added methyl N-(2,2-diethoxyethyl)glycinate (1 eq) (prepared as described in Synthesis 2002, 2, 242-252), and the mixture was stirred at RT for 2 h. The reaction was diluted with EtOAc, washed sequentially with 1N HCl, sat. aq. NaHCO3 solution, and then with brine. The organic layers were dried (Na2SO4), filtered and concentrated and concentrated under reduced pressure. MS (ES) C23H30FN3O6 required: 463, found: 464 (M+H)+; 486 (M+Na)+.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][CH2:18]3)[CH2:13][C:12]2=[O:29])=[CH:7][CH:6]=1)=[NH:4].O.[OH-].[Li+].[Cl-].[NH4+]>O>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]3)[CH2:13][C:12]2=[O:29])=[CH:9][CH:10]=1)=[NH:4]
Reactant: CCOC(=O)CN1CCC(N2CCN(c3ccc(C(=N)NO)cc3)C(=O)C2)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Product: N=C(NO)c1ccc(N2CCN(C3CCN(CC(=O)O)CC3)CC2=O)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Ethyl 4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate (0.8 g) was dissolved in 8 ml of water, and 0.21 g of lithium hydroxide monohydrate was added with ice-cooling. The mixture was stirred for 30 minutes with ice-cooling, an aqueous saturated ammonium chloride solution was added, and the mixture was concentrated. The crystals formed were collected by filtration to give 0.67 g of 4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[OH-].[K+].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15]Br>CS(C)=O.O>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: COC(CBr)OC
Reactant: Cc1cc(O)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(COc1ccc(F)c(C)c1)OC

Procedure:
A mixture of 4-fluoro-3-methylphenol (36.7 g), potassium hydroxide pellets (19.5 g) and bromoacetaldehyde dimethyl acetal (34.6 ml) in dimethyl sulphoxide (240 ml) was heated at 110° for 24 h. The mixture was cooled, diluted with water (350 ml) and extracted with hexane. Evaporation of the extracts gave the title compound as an oil (52.3 g).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:8]([O:13]C)([O:11][CH3:12])[O:9][CH3:10]>>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][P:8]([O:11][CH3:12])([O:9][CH3:10])=[O:13])[CH3:7]
Reactant: COP(OC)OC
Reactant: CCOC(=O)CCl
Product: CCOC(=O)CP(=O)(OC)OC
Temperature: 130 °C
Reaction time: 10 h

Procedure:
An amount of 340.8 g of ethyl chloroacetate was mixed with 496 g of trimethyl phosphite in a reactor fitted with a thermometer, nitrogen inlet and a fractionation column (containing 5 mm Raschig rings as packing) topped with a variable reflux condenser. The reactor was heated to enable slow reflux in the column only followed by a slow increase in the temperature from 110 to 150 degrees C. over 10 hours and maintained at about this temperature. The pressure was reduced to 11 mm Hg and volatile material was removed on heating the reactor slowly from 50 to 140 degrees C. The yield of the pure product obtained was 85%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:38]=[CH:37][C:22]([CH2:23][N:24]6[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12]([S:39]([C:42]4[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:20]=[CH:21][C:22]([CH2:23][N:24]6[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]6)=[CH:37][CH:38]=5)[CH:17]=4)[N:12]([S:39]([C:42]4[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=4)(=[O:41])=[O:40])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNCC5)cc4)cnc32)cc1
Yield: 98.5 %

Procedure:
tert-butyl 4-(4-(3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperazine-1-carboxylate (500 mg) was suspended in 6 mL of dichloromethane and treated with TFA (5 mL) and reacted for 30 minutes. The solvent was removed in vacuo and the residue washed with 1 N sodium hydroxide solution, water and brine and dried over MgSO4 to yield 418 mg of crude product that was used without further purification (562 M+H).
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C:42]1([CH2:46][OH:47])[CH2:45][CH2:44][CH2:43]1>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:41][C:42]4([CH2:46][OH:47])[CH2:45][CH2:44][CH2:43]4)=[O:40])=[CH:11][CH:12]=3)[CH:21]=2)[CH:27]=1
Reactant: NC1(CO)CCC1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3(CO)CCC3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (1-aminocyclobutyl)methanol (27 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (54 mg, 53%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O=C1CCC(c2cccc(O)c2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(C2=NNC(=O)CC2)c1

Procedure:
i. A stirred mixture of finely powdered 6-(3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (13.1g, 0.07 mole), potassium carbonate (9.5g, 0.07 mole), allyl bromide (11.75 ml, 0.14 mole), and dry acetone (250 ml) was heated under reflux for 18 hours. Evaporation of the filtered solution under reduced pressure gave 6-(3-allyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone which was washed with ether (13.66g, 86%, m.p. 111°-113° C). Crystallisation from a small volume of ethanol gave the pure pyridazinone m.p. 112°-114° C.