Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([OH:19])=[C:14]([Cl:20])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC1C=CC=CC=1C>[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:14]([Cl:20])[CH:13]=1
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Reactant: O=C(O)c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: O=C(O)c1cnccc1Oc1cc(Cl)c(Br)cc1Cl
Temperature: 120 °C

Procedure:
To a stirred suspension of 6.0 g (38.08 mmol) 4-chloronicotinic acid (commercially available; CAS RN 10177-29-4) in 200 mL o-xylene were added 10.13 g (41.89 mmol) 4-bromo-2,5-dichlorophenol (commercially available; CAS RN 1940-42-7) and 2.84 g (7.62 mmol) tetrakis-(acetonitrile)-copper hexafluorophosphate (commercially available; CAS RN 64443-05-6). Then 31.31 g (95.20 mmol) cesium carbonate were added and the resulting dark brown suspension as heated to 120° C. for 16 hours. After cooling to room temperature, the sovent was evaporated, the residue dissolved in 1.25 l water, extracted four times with 250 mL ethyl acetate and filtered. The pH of the green filtrate was adjusted to 6 using 25% aqueous hydrochloric acid. The formed precipitate was filtered off to give a first batch of the desired compound. The pH of the filtrate was adjusted to pH 3 using 25% aqueous hydrochloric acid, the suspension stirred for 0.25 hours at room temperature and then kept in the fridge for 64 hours. The suspension was filtered and washed with water to yield another batch of compound. Brown solid (overall yield 5.63 g (41%)). MS (ESI): m/z=363.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:4][N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1>>[ClH:1].[ClH:1].[CH3:15][O:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[C:11]2[C:6]=1[C:5]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[N:4][N:3]=[C:2]2[NH:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)[CH2:29][CH2:30]1
Reactant: COc1ccc(-c2nnc(Cl)c3cc(OC)cc(OC)c23)cc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(OC)cc(OC)c23)cc1
Product: Cl

Procedure:
This compound is obtained according to the procedure described in 2.4 by reacting 4-chloro-6,8-dimethoxy-1-(4-methoxyphenyl)phthalazine described in 2.3 with 4-amino-1-(naphthalen-2-ylmethyl)piperidine. On treatment with hydrochloric ether, a precipitate forms, which is filtered off, washed with ethyl ether and dried under reduced pressure. The hydrochloride obtained is in the form of a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1.[CH3:20]I.O>CN1C(=O)CCC1>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=2)=[N:12]1
Reactant: CSc1nccc(-c2n[nH]c3ccccc23)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1nccc(-c2nn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 99 mg, 2.47 mmol) was added to a stirring solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole (520 mg, 2.15 mmol) in NMP at 0° C. The mixture was stirred for 15 min and then methyliodide (0.14 mL, 2.25 mmol) was added and the resulting mixture was stirred for 2 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc, 9/1) to give 415 mg of 1-methyl-3-(2-methylsulfanylpyrimidin-4-yl)-1H-indazole.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH2:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)[CH3:40]>>[NH2:30][C:29]1[S:28][C:27]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:39][CH3:40])[CH:46]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCc1cccc(B(O)O)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: CCc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1
Yield: 29 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-ethylphenyl boronic acid gave 267 as an off-white solid (25 mg, 29% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.89 (s, 1H), 7.71 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.43-7.33 (m, 4H), 7.26 (d, J=7.8 Hz, 1H), 3.64 (s, 3H), 3.14-2.98 (m, 4H), 2.67 (q, J=7.6 Hz, 2H), 2.46 (d, J=5.7 Hz, 2H), 1.77 (d, J=11.7 Hz, 2H), 1.32-1.19 (m, 6H). Alkyl NH2 not seen. LCMS (ES+) m/z 440 (M+1)
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>O1CCCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: COc1ccccc1N=C=O
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccccc3OC)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-methoxyphenyl isocyanate (427 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 48 hours under N2 atmosphere at RT (35° C.). The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product (10e), which was finally chromatographed using chlorophorm-hexane (1:19) to give 10e as solid. Yield: 480 mg, 66.80%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:20]1CCOC[CH2:21]1.O=C(Cl)OC(Cl)(Cl)Cl>O>[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:21](=[O:20])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:16][CH2:15]1)(=[O:19])[CH3:18]
Reactant: C1COCCO1
Reactant: CC(=O)N1CCN(c2ccc(N)c(C(=O)O)c2)CC1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)N1CCN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC1

Procedure:
To the mixture of 18 g 2-amino-5-(4-acetylpiperazin-1-yl)benzoic acid and 60 ml dioxane, 10 ml diphosgene is added dropwise under stirring and cold water cooling. The mixture is then heated at reflux temperature for 2 hours. After cooling the solid material is filtered off, washed with 50 ml ether and dried. 24 g of the title compound is obtained (MH+: 290).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH2:18][CH2:17]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A suspension of 4-acetylaminobenzene sulfonyl chloride (4.5 mmol) in anhydrous CH2Cl2 at room temperature is treated with 1-methyl piperazine (4.5 mmol) and triethylamine (4.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, water was added, and the product extracted with additional CH2Cl2 The combined organic extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure, affording the desired N-[4-(4-methylpiperazine-1-sulfonyl)phenyl]acet-amide. Mp: 184° C.; Yield 41%; 1H NMR (DMSO d6): δ 2.09 (s, 3H), 2.15 (s, 3H), 2.40 (m, 4H), 2.85 (m, 4H), 7.63-7.68 (d,2H, J=10 Hz), 7.80-7.84 (d, 2H, J=8 Hz), 10.41 (s, 1H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:18]1[CH2:22][S:21][CH2:20][CH:19]1[C:23](OC)=[O:24].C(C1C=CN=C(N2C([O-])=C3CSCC3=N2)C=1)C.[Na+:44]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:1]3[C:23]([O-:24])=[C:19]4[CH2:20][S:21][CH2:22][C:18]4=[N:2]3)[CH:8]=2)[CH:12]=1.[Na+:44]
Reactant: COC(=O)C1CSCC1=O
Reactant: NNc1cc(OCc2cccnc2)ccn1
Agent: CCc1ccnc(-n2nc3c(c2[O-])CSC3)c1
Agent: [Na+]
Product: [O-]c1c2c(nn1-c1cc(OCc3cccnc3)ccn1)CSC2

Procedure:
According to the process described in Example 8, starting with 197 mg of 2-hydrazinyl-4-(pyridin-3-ylmethoxy)pyridine and 146 mg of methyl 4-oxotetrahydrothiophene-3-carboxylate, 225 mg of sodium 2-(4-ethylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate are obtained in the form of a white lyophilizate.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([O:28]C(C)(C)C)=O)[C@H:21]3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14]2)=[CH:9]1.[OH-].[Na+].[C:35]([NH:43][C@@H:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1C(O)=O)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>O>[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([C@H:45]4[CH2:46][CH2:47][CH2:48][C@H:44]4[NH:43][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:28])[C@H:21]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14]2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21
Reactant: O=C(N[C@@H]1CCC[C@@H]1C(=O)O)c1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@@H]1CCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 44.1 %

Procedure:
TFA (1 ml) was added to tert-butyl (3aR*,4R*,9bR*)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (178 mg, 0.5 mmol), and the mixture was stirred at room temperature for 3 min. Ice was added to the reaction solution, the mixture was basified with 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 ml), and (1S,2R)-2-(benzoylamino)cyclopentanecarboxylic acid (117 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) were added. DEPC (82 mg, 0.5 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (5:1-2:1, v/v) to give the title compound (104 mg, 44%) as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:6]([NH:14][C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N+:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)([O-:30])=[O:29].O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=2)=[O:12])=[C:6]([NH:14][C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetic acid (10.9 g) prepared by step g) and triethylamine (11 mL) in DMF (100 mL) was added at room temperature p-nitrobenzyl bromide (17.0 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated brine (500 mL) and water (300 mL), and the mixture was extracted with ethyl acetate (200 mL, 2×100 mL). The organic layers were combined, washed with saturated brine (100 mL), dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified with column chromatography (SiO2 300 g, hexane/ethyl acetate/chloroform=3:1:4˜0:1:1) to give the object compound (16.4 g, 98%) as a pale brown solid. Further the product was recrystallized from chloroform/hexane to give the object compound (10.4 g, 64%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Br[C:17]1[C:22]([F:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.Cl>CS(C)=O.O>[F:23][C:22]1[C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1)C(=O)O
Temperature: 48 °C

Procedure:
2-(4-Hydroxyphenoxy) propanoic acid (1.80 g, 0.00988 mole) was dissolved in 15 ml of dimethyl sulfoxide. A solution of sodium hydroxide (0.8 g, 0.02 mole in 1 ml of water) was added and the reaction mixture was heated under nitrogen to 48° C. over a 27 minute period. 2-Bromo-3-fluoro-5-(trifluoromethyl)pyridine (2.40 g, 0.00984 mole) dissolved in 5 ml of dimethyl sulfoxide was added and the reaction mixture was heated at 75°-78° C. for 40 minutes. The mixture was poured into 150 ml of cold water and acidified with aqueous HCl. A gum came down. Upon work-up and purification, a fraction (0.45 g) was obtained which had an elemental analysis of, in percent by weight:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24](COCC[Si](C)(C)C)[C:17]=23)[CH:12]=[CH:11][N:10]=1.FC1C=CC(F)=CC=1C1C=C(NC2C3C(=CN(COCC[Si](C)(C)C)N=3)N=CC=2)C=CN=1.[F:65][C:66]([F:71])([F:70])[C:67]([OH:69])=[O:68]>C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[CH:12]=[CH:11][N:10]=1.[C:67]([OH:69])([C:66]([F:71])([F:70])[F:65])=[O:68]
Reactant: C[Si](C)(C)CCOCn1ncc2nccc(Nc3ccnc(-c4cc(F)ccc4F)c3)c21
Agent: C[Si](C)(C)CCOCn1cc2nccc(Nc3ccnc(-c4cc(F)ccc4F)c3)c2n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)ccn2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-(2-(2,5-difluorophenyl)pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(2,5-difluorophenyl)pyridin-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-amine (1.2 g, 3.2 mmol) were combined with trifluoroacetic acid (1.1 mL) and stirred at 70° C. for 15 minutes. Anisole (20 μL) was then added and the mixture was further heated at 70° C. The reaction mixture was then purified via preparative HPLC using a gradient of 10-30% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.39-7.52 (m, 4H) 7.79 (br. s., 2H) 7.95 (s, 1H) 8.57 (d, J=6.32 Hz, 2H) 8.76 (br. s., 2H). MS [M+H] found 324.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.NCC1C=CC(C(OC)=O)=CC=1[F:42]>>[F:42][C:29]1[CH:28]=[C:23]([CH:22]=[CH:21][C:20]=1[CH2:19][NH:18][C:16]([C:4]1[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:17])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reactant: COC(=O)c1ccc(CN)c(F)c1
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(aminomethyl)-3-fluorobenzoate: 1H-NMR (CDCl3) δ 8.45–8.33 (2H, m), 8.04 (1H, d, J=3.1 Hz), 7.80 (1H, dd, J=7.9, 1.5 Hz), 7.71 (1H, dd, J=10.5, 1.5 Hz), 7.49 (1H, t, J=7.6 Hz), 7.17–7.12 (4H, m), 4.78 (2H, d, J=6.1 Hz), 3.91 (3H, s); MS (ESI) m/z 417 (M+H)+, 415 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)CC)C.[CH2:27]([P:34](Cl)([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])(OCC1C=CC=CC=1)OCC1C=CC=CC=1.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH2:36]([P:34]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=P(Cl)(Cc1ccccc1)Cc1ccccc1
Agent: COC(=O)CN
Agent: Cl
Agent: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](Cc1ccccc1)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2g of L-phenylalanine-glycine methyl ester hydrochloride (7.4 mmoles) are put in suspension in 20 ml of anhydrous chloroform. 1.50 g of triethylamine (15 mmoles) are added. The solid enters into solution. The solution is cooled to 0° C. and 2.17 g (7.4 mmoles) of dibenzyl phosphoryl chloride freshly prepared from dibenzyl phosphite and sulfuryl chloride are added while stirring for 30 minutes. The mixture is allowed to stand for 20 hours at room temperature. The precipitate formed is filtered and the filtrate is washed in succession with 30 ml of 1N HCl, 20 ml of water, 20 ml of 10% bicarbonate, then 2×30 ml of water. The organic solution is dried on anhydrous Na2SO4 and evaporated under a vacuum. A pale yellow solid is obtained which is recrystallized in ethyl acetate.
Reaction SMILES: [CH3:1]COCC.C[Si](C=[N+]=[N-])(C)C.[Cl:13][C:14]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CC(O)=O>C1COCC1.CO>[Cl:13][C:14]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[C:16]([O:18][CH3:1])=[O:17]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C)nc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 2 M ether solution of (trimethylsilyl)diazomethane (30 mL, 60.0 mmol) was added to a solution of 2-chloro-6-methylnicotinic acid (8 g, 45.2 mmol) in THF (100 mL) and MeOH (25 mL) in a room temperature water bath. After 30 min, HOAc (2 mL) was added. The mixture was concentrated and purified by silica gel chromatography, eluting with 0-20% EtOAc in hexanes, to give methyl 2-chloro-6-methylnicotinate as colorless oil (7.77 g, 93% yield). MS (ES+) m/z: 186 (M+H); LC retention time: 2.64 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][C:20]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)([C:23]([F:26])([F:25])[F:24])[CH2:19]2)[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][C:20]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)([C:23]([F:26])([F:25])[F:24])[CH2:19]2)[CH:15]=[CH:14][C:3]=1[C:4](=[S:44])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NCc1ccccn1)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(c2ccc(C(=S)NCc3ccccn3)c(Cl)c2)C1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
To the solution of 2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin1-yl]-N-(pyridin-2-ylmethyl)benzamide (0.35 g) in toluene was added Lawesson reagent (0.28 g) and the mixture was heated to reflux for 3 hours. After the mixture was cooled to room temperature, the solvent was distilled away under the reduced pressure, and the residue was purified by silica gel chromatography to yield 2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin1-yl]-N-(pyridin-2-ylmethyl)benzenecarbothioamide (0.10 g). 1H-NMR (CDCl3) δ: 2.51-2.61 (1H, m), 2.84-2.92 (1H, m), 3.45-3.61 (2H, m), 3.79 (1H, d), 4.08 (1H, d), 5.08 (2H, d), 6.49-6.54 (2H, m), 7.22-7.28 (3H, m), 7.36 (1H, d), 7.40 (1H, t), 7.72 (1H, td), 7.79 (1H, d), 8.54 (1H, d), 9.27 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH:6]=2)([O-])=O>CCOC(C)=O.[Pd]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=[C:4]2[NH2:1])=[N:8]1
Reactant: O=[N+]([O-])c1cccc2nn(C3CCCCO3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2nn(C3CCCCO3)cc12
Reaction time: 16 h
Yield: 28.4 %

Procedure:
A solution of 4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (2.336 g, 9448 μmol) was dissolved in EtOAc (100 mL) and treated with 10% Pd/C (100 mg). The resulting suspension was stirred under an atmosphere of H2. for 16 h after which time reduction was complete. The reaction mixture was filtered, concentrated and purified by flash chromatography on silica (50% EtOAc/hexane) to give 2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (584 mg, 28.5% yield) as a dry orange foam. 1H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H); 6.92 (t, J=7.82 Hz, 1H); 6.72 (d, J=8.61 Hz, 1H); 5.99 (d, J=7.04 Hz, 1H); 5.54-5.69 (m, 3H); 3.98 (d, J=11.74 Hz, 1H); 3.63-3.78 (m, 1H); 2.02-2.13 (m, 2H); 1.87-2.00 (m, 1H); 1.65-1.80 (m, 1H); 1.59 (br. s., 2H). m/z (ESI, +ve). Found 218.1 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccccc1CBr
Temperature: 2.5 °C

Procedure:
To a solution of 97.0 g (0.646 mol) o-tolylacetic acid in 1.75 L carbon tetrachloride was added 115.0 g (0.646 mol) N-bromosuccinimide and 3.4 g (0.021 mol) 2,2′-azobisisobutyronitrile. The mixture was heated at reflux under a nitrogen atmosphere for 4 h. After the mixture was cooled to 0-5° C. for 30 min, the solids were removed by filtration and washed with a small portion of carbon tetrachloride. This solid was triturated with water (0.8 L), collected on a filter, and washed with 500 mL of water to give 2-bromomethylphenylacetic acid. The filtrate was concentrated to a volume of 150 ml, and the resulting slurry cooled to 0-5° C. for 30 min. A second batch of product was obtained.