Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:39])[NH:14][C@@H:15]1[CH2:20][CH2:19][C@@H:18]([CH2:21][CH:22]2[O:37][C:25]3[CH:26]=[N:27][C:28]4[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([F:34])[C:33]=4[C:24]=3[CH:23]2[OH:38])[O:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9].[C:40](OC(=O)C)(=[O:42])[CH3:41].CCCCCC>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:8]([O:12][C:13]([NH:14][C@H:15]1[CH2:16][O:17][CH:18]([CH2:21][C@@H:22]2[O:37][C:25]3[CH:26]=[N:27][C:28]4[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([F:34])[C:33]=4[C:24]=3[CH:23]2[O:38][C:40](=[O:42])[CH3:41])[CH2:19][CH2:20]1)=[O:39])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2ncc3c(c2c1F)C(O)C(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COc1ccc2ncc3c(c2c1F)C(OC(C)=O)[C@H](CC1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
4-Dimethylaminopyridine (16 mg, 0.13 mmol, 0.5 eq) and triethylamine (112 μL, 0.80 mmol, 3.0 eq) are added at 0° C. to a stirred solution of (3R,6S)-[6-(9-fluoro-1-hydroxy-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-ylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (120 mg, 0.27 mmol, 1.0 eq) in dichloromethane (10 mL), followed by acetic anhydride (38 μL, 0.40 mmol, 1.5 eq). After 1 hour stirring at 0° C., the reaction mixture is quenched with ethanol (1 mL), solvents are evaporated to give a crude product that is purified by column chromatography (silica gel, eluent: n-hexane:ethyl acetate, 5:1 to 1:1, v/v) to afford acetic acid 2-(2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-ylmethyl)-9-fluoro-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-1-yl ester as a light yellow solid (89 mg, 68% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]([C:11]#[N:12])[CH3:10])(C)(C)C.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>ClCCl>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[NH2:12][CH2:11][C@@H:9]([CH3:10])[C:8]#[N:7]
Reactant: C[C@@H](C#N)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C#N)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
((R)-2-Cyano-2-methyl-ethyl)-carbamic acid tert-butyl ester (42 mg, 0.23 mmol) was dissolved in dichloromethane (1.2 ml) and cooled in an ice bath. Trifluoroacetic acid (0.7 ml) was slowly added and the reaction was stirred at room temperature for 3 h then evaporated and dried under high vacuum to afford (R)-3-amino-2-methyl-propionitrile trifluoroacetate which was used without further purification.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(F)c2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(F)c2)C1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A suspension of (R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (12 g, 31.75 mmol) and Pd(OH)2/C (1.2 g) in MeOH (240 ml) was stirred under H2 for 1 hr. The mixture was filtered and evaporated under reduced pressure to give desired (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (10 g).
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]=[CH:13][CH:12]=4)[NH:9][C:10]=31)[CH2:4][CH2:3]2.I[CH2:26][CH3:27]>CN(C)C=O>[CH2:26]([N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc4ccccc34)c(=O)c12
Reactant: CCI
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1cccc3ccccc13)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 46; 150 mg, 0.47 mmol) and iodoethane (151 μL, 1.88 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 12 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-1-ethyl-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (72 mg, 44%) as a light yellow foam. ES(+)-MS (M+H) 347.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:2]=1.[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:15]([NH:21][C:22]([N:11]1[CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=c1[nH]cc(-c2cccnc2)c(=O)[nH]1
Reactant: CCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCCNC(=O)n1cc(-c2cccnc2)c(=O)[nH]c1=O
Yield: 57 %

Procedure:
The title compound was obtained according, to the procedure described for the synthesis of Example 1, starting from 5-(3-pyridyl)-1H-pyrimidine-2,4-dione (0.067 g, 0,198 mmol). Herein, 2 equivalents of DMAP and 2.7 equivalents of hexyl isocyanate in 4 mL pyridine were used. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 40:60) to afford the title compound (0.04 g, 57%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=6.0 Hz, 3H), 1.29-1.41 (m, 6H), 1.58-1.67 (m, 2H), 3.42 (dt, J=7.1, 5.5 Hz, 2H), 7.37 (ddd, J=8.0, 4.9, 0.9 Hz, 1H), 7.97 (td, J=8.0, 2.0 Hz, 1H), 8.64 (dd, J=4.9, 1.7 Hz, 1H), 8.66 (s, 1H), 8.80 (dd, J=2.4, 0.9 Hz, 1H), 9.11 (t, J=5.0 Hz, 1H), 9.21 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 14.13, 22.66, 26.64, 29.29, 31.51, 41.58, 77.16, 113.74, 123.50, 127.93, 136.39, 136.58, 148.70, 149.48, 149.74, 151.09, 161.30. MS (ESI) m/z: 317 (M-Hr.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:13])[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.O>[Cl:16][C:17]1[N:18]=[C:19]([NH:13][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][CH3:12])[CH:20]=[N:21][CH:22]=1
Reactant: CCCC(N)c1ccc(C(F)(F)F)cc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(Nc1cncc(Cl)n1)c1ccc(C)cc1
Temperature: 25 °C
Yield: 5.7 %

Procedure:
To a solution of 1-[4-(trifluoromethyl)phenyl]butan-1-amine (0.40 g, 1.9 mmol) and 2,6-dichloropyrazine (0.55 g, 3.7 mmol) in 1,4-dioxane (6 mL) was added anhydrous potassium carbonate (0.39 g, 2.8 mmol). The resulting mixture was heated at reflux for 18 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and H2O. The organic phase was collected, dried and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give pure product (0.03 g, 5%).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[CH3:51][N:52]([CH2:54][C:55]1[N:60]=[C:59]([NH2:61])[CH:58]=[CH:57][N:56]=1)[CH3:53]>C(Cl)Cl>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:61][C:59]3[CH:58]=[CH:57][N:56]=[C:55]([CH2:54][N:52]([CH3:53])[CH3:51])[N:60]=3)=[O:23])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CN(C)Cc1nccc(N)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CN(C)Cc1nccc(NC(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)N2C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
1-Methylimidazole (178 μl, 2.232 mmol) was added into the solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (400 mg, 0.744 mmol) in DCM (4.08 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (60.5 μl, 0.781 mmol) was added dropwise at 0° C. To the reaction mixture was added 2-[(dimethylamino)methyl]-4-pyrimidinamine (147 mg, 0.967 mmol) in 1 ml of DCM. After stirring for 1.5 hrs at ambient temperature, the solvent was removed under reduced pressure to give a residue which was purified by RP-HPLC to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3[({2-[(dimethylamino) methyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidine carboxylate (104 mg, 0.147 mmol, 20% yield). MS (ES+) m/z 672.2 (MH+).
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13](I)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[C:10]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.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.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[C:1]([N:9]1[C:14](=[O:15])[C:13]([C:29]2[C:24]([CH3:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[C:10]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncccc1B(O)O
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCCl)c1=O
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: COCCOC
Solvent: O
Product: Cc1ncccc1-c1cn(CCCCCl)c(=O)n(C(=O)c2ccccc2)c1=O
Yield: 66.4 %

Procedure:
3-Benzoyl-1-(4-chloro-butyl)-5-iodo-1H-pyrimidine-2,4-dione (Prep 44, 541 mg, 1.25 mmol) was dissolved in degassed DME-water solution (5-1, 37.5 mL). 2-Methyl-pyridine 3-boronic acid (325 mg, 1.9 mmol), Na2CO3 (265 mg, 2.5 mmol), 2-(dicyclohexylphosphino)biphenyl (52 mg, 0.15 mmol) and Pd(PPh3)4 (288 mg, 0.25 mmol) were added and the mixture was refluxed for 3 hours. A second batch was run in parallel in the same reaction conditions on 3-Benzoyl-1-(4-chloro-butyl)-5-iodo-1H-pyrimidine-2,4-dione (Prep 44, 108 mg, 0.25 mmol) using 2-Methyl-pyridine 3-boronic acid (65 mg, 0.375 mmol), Na2CO3 (53 mg, 0.5 mmol), 2-(dicyclohexylphosphino)biphenyl (17.5 mg, 0.05 mmol) and Pd(PPh3)4 (57.75 mg, 0.05 mmol) dissolved in degassed DME-water solution (5-1, 7.5 mL). The crudes were then mixed and the solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) and then loaded on SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5 to give the title compound (330 mg, 56% yield).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][CH:18]1[CH2:20][CH:19]1[C:21](Cl)=[O:22]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:21]([CH:19]3[CH2:20][CH:18]3[CH3:17])=[O:22])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CC1CC1C(=O)Cl
Product: CCC(NC(=O)C1CC1C)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 90 mg (0.74 mmol) 2-methyl-cyclopropylcarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:31]2[CH2:32][CH2:33][N:28]([C:26](=[O:27])[CH2:25][N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=4)=[C:2]([Cl:1])[C:3]([C:14]([F:15])([F:17])[F:16])=[N:4]3)[CH2:29][CH2:30]2)=[CH:35][C:36]=1[O:41][CH3:42]
Reactant: Fc1cccc(-c2[nH]nc(C(F)(F)F)c2Cl)c1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3-c3cccc(F)c3)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-[3-Fluorophenyl]-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.59) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.64–7.68 (d, 1H), 7.56–7.62 (d, 1H), 7.36–7.42 (m, 1H), 7.22–7.24 (m, 2H), 7.08–7.12 (m, 1H), 6.42–6.52 (m, 2H), 5.2 (s, 2H), 3.9 (s, 3H), 3.62–3.82 (m, 4H), 3.12–3.22 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([OH:33])[C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:33][CH:17]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:21][CH:22]=1)[CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([F:1])[CH:14]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCC(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F)C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCC(Oc1ccc(CCC(OCc2ccccc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F)C(=O)O

Procedure:
2-(4-(3-(Benzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2-fluoro-phenoxy)butanoic acid is prepared from 2-(2-fluoro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)butanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of benzyl bromide according to general procedure H.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:29])([F:28])[C:7]1[NH:8][C:9]([C:24]([F:27])([F:26])[F:25])=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([CH3:18])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].N([O-])=O.[Na+]>O>[F:29][C:6]([F:5])([F:28])[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([C:24]([F:25])([F:27])[F:26])[N:8]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
A 50 ml round bottomed flask is charged with 20 ml of glacial acetic acid. To this is added 5 g (0.0133 mole) of diethyl 2,6-bis(trifluoromethyl)-4-methyl-1,4-dihydro-3,5-pyridinedicarboxylate, followed by a slow addition of 3 g (0.0434 mole) of sodium nitrite. The flask is immediately fitted with a condenser and nitrogen line, the stirring continued for 18 hours, and the mixture is poured over crushed ice and water. The organics are extracted twice with ether, washed once with saturated aqueous sodium chloride and washed twice with saturated aqueous sodium bicarbonate solution. The organics are dried over anhydrous magnesium sulfate and concentrated yielding 2.16 g (43.5%) of product, m.p. 55°-58° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:12]1[C:11]([O:10][CH3:9])=[CH:16][C:15]([O:17][CH3:18])=[CH:14][C:13]=1[P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: CCOP(=O)(OCC)c1cc(OC)cc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1cc(OC)cc(OC)c1Br
Temperature: 0 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
N-Bromosuccinimide (NBS) (8.9 g, 50 mmol) was added to the solution of diethyl 3,5-dimethoxyphenylphosphonate (12.5 g, 45.6 mmol) in CH2Cl2 (150 ml) at 0° C. The resulting suspension was stirred at 0° C. for 6 h. Na2CO3 (saturated, 60 ml) was added to quench the reactions. It was stirred at RT for 30 min, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (80 ml×1). The combined organic layer was washed with brine and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow oil (14 g, 87% yield). It was sufficiently pure enough for the next step. The pure sample was obtained by chromatography. 1H NMR (300 MHz, CD2Cl2) δ: 7.16 (dd, J1=3.0 Hz, J2=15.3 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 4.20-4.06 (m, 4H), 3.89 (s, 3H), 3.85 (s, 3H), 1.34 (t, J=7.2 Hz, 6H). 31P NMR (121.5 MHz, CD2Cl2) δ: 15.59. 13C NMR (75.5 MHz, CD2Cl2) δ: 159.77 (d, Jc-p=20.0 Hz), 157.66 (d, Jc-p=19.0 Hz), 131.49 (d, Jc-p=189.2 Hz), 112.04 (d, Jc-p=8.7 Hz), 105.52 (d, Jc-p=4.5 Hz), 103.51 (d, Jc-p=2.9 Hz), 62.73, 62.66, 56.78, 55.96, 16.34, 16.26.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([S:45][CH3:46])[N:40]=2)=[CH:36][CH:35]=1>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[S:38][C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([S:45][CH3:46])[N:40]=3)=[CH:36][CH:35]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CSc1nccc(-c2ccc(Br)s2)n1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nccc(-c2ccc(-c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)s2)n1

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with 4-(5-bromothien-2-yl)-2-(methylthio)pyrimidine (145 mg, 0.5 mmol). The crude residue stirred in ethyl acetate/water for 1 hour before being filtered, and the aqueous removed using a Varian Chem Elut Column (CE1010). The resulting solution was concentrated and recrystallised from methanol to give the title compound; Mass Spectrum: M+H+-Boc 463.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:11]([CH3:25])([CH3:24])[CH2:10]2)=[O:4].ON1C2C=CC=CC=2N=N1.[CH3:36][N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]=C=NCC.Cl.CN1CCOCC1.CN1CCC(N)C1>ClCCl>[CH3:25][C:11]1([CH3:24])[CH2:10][C:9]2[C:14](=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:41][CH:40]2[CH2:39][CH2:38][N:37]([CH3:36])[CH2:46]2)[CH:16]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1cccc2c1NC(c1cccc(C(=O)O)c1)C(C)(C)C2
Agent: CN1CCC(N)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc2c1NC(c1cccc(C(=O)NC3CCN(C)C3)c1)C(C)(C)C2
Reaction time: 1 h

Procedure:
To a suspension of 3-(8-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (63 mg, 0.19 mmol) in dichloromethane (5.0 mL) was added N-hydroxybenzotriazole (37.6 mg, 0.28 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (106.7 mg, 0.56 mmol), followed by 4-methylmorpholine (56.3 mg, 0.56 mmol) and the resultant mixture was stirred at room temperature for 1 h., then 1-methylpyrrolidin-3-amine (27.9 mg, 0.28 mmol) was added to the flask and the reaction mixture was stirred for an additional 1 h. LC-MS showed the reaction was complete. The reaction was quenched with water and separated. The aqueous layer was extracted with dichloromethane (twice) and the combined organic layers were washed with 5% sodium hydroxide aqueous solution (twice) and water (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 76 mg of methyl 3,3-dimethyl-2-(3-(1-methylpyrrolidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate as a white solid, which was used in next step without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2=CS(=O)(=O)CC2)cc1OC1CCCC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2CCS(=O)(=O)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
A stirred solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydrothiophene 1,1-dioxide (1.2 g; which is prepared as described in Example 13) in ethanol (50 mL) is treated with sodium borohydride (0.45 g) followed by cobalt dichloride hexahydrate (0.94 g), and the purple mixture is stirred at room temperature for 6 hours. It is then filtered through a pad of diatomaceous earth, and the pad is washed with dichloromethane (150 mL). The combined flitrate and washings are evaporated, and the resulting residue is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and toluene as eluent, to give an oil which slowly crystallizes. It is recrystallized from ethyl acetate at -40° C., to give 3-(3-cyclopentyloxy-4methoxyphenyl)tetrahydrothiophene 1,1-dioxide (0.74 g) in the form of a white solid, m.p. 89°-90° C. [Elemental analysis: C,61.8; H,7.10; S,10.4%; calculated: C,61.91; H,7.1; S,10.33%].
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][C:15]3=[C:18]([C:21]([NH2:23])=[O:22])[NH:19][N:20]=[C:14]3[CH2:13]2)=[N:10][CH:11]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[NH:35][C:36](=[O:37])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][C:15]3=[C:18]([C:21]([NH2:23])=[O:22])[NH:19][N:20]=[C:14]3[CH2:13]2)=[N:10][CH:11]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]nc2c1CCN(c1ccc(N)cn1)C2
Agent: NC(N)=O
Product: NC(=O)c1[nH]nc2c1CCN(c1ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cn1)C2

Procedure:
The urea function is introduced onto the 6-(5-aminopyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the method described in Example 1, using 2-fluoro-5-(trifluoromethyl)phenyl isocyanate, and results in the obtaining of 6-{5-[3-(2fluoro-5-trifluoromethylphenyl)-ureido]pyridin-2-yl}-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxamide.