Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19]O)=[N:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:40]N1C(=O)CCC1=O>C(Cl)Cl>[Br:40][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)=[CH:18][N:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)c(F)c2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(-c2ccc(CBr)nc2)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A solution of alcohol 106 (678 mg, 2.36 mmol) and triphenylphosphine (746 mg, 2.84 mmol) in anhydrous CH2Cl2 (30 mL) was carefully treated with recrystallized N-bromosuccinimide (507 mg, 2.85 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (25 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 10-20% Et2O/pentane gave 2-(bromomethyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]pyridine (107) (616 mg, 75%) as a white solid that was used directly in the next step; 1H NMR (CDCl3) δ 8.76 (dd, J=2.4, 0.6 Hz, 1H), 7.84 (dd, J=8.1, 2.4 Hz, 1H), 7.54 (dd, J=8.0, 0.6 Hz, 1H), 7.46-7.33 (m, 3H), 4.60 (s, 2H); HRESIMS calcd for C13H9BrE4NO m/z [M+H]+ 351.9778, 349.9798, found 351.9778, 349.9798.
Reaction SMILES: [Si:1]([O:18][CH:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24]([N:31]2[CH2:36][CH2:35][NH:34][C@H:33]([CH3:37])[CH2:32]2)=[CH:23][CH:22]=[C:21]3[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:43][CH2:44][C@H:45]1[C:50]2[CH:51]=[CH:52][C:53]([C:55]([NH2:57])=[O:56])=[CH:54][C:49]=2[CH2:48][CH2:47][O:46]1)(=O)=O>>[Si:1]([O:18][CH:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24]([N:31]2[CH2:36][CH2:35][N:34]([CH2:43][CH2:44][C@H:45]4[C:50]5[CH:51]=[CH:52][C:53]([C:55]([NH2:57])=[O:56])=[CH:54][C:49]=5[CH2:48][CH2:47][O:46]4)[C@H:33]([CH3:37])[CH2:32]2)=[CH:23][CH:22]=[C:21]3[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C3)CCN1
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21

Procedure:
(3R)-1-(1-{[tert-Butyl(diphenyl)silyl]oxy}-1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine was condensed with 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, as described for Example 1b).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH:18]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH:38]=2)=[O:35])[C:17]1=[O:50])=[O:14])(C)(C)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:49][S:46]([NH:45][C:43]([C:39]1[CH:38]=[C:37]([NH:36][C:34](=[O:35])[NH:33][CH:18]2[C:17](=[O:50])[N:16]([CH2:15][C:13]([OH:14])=[O:12])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19]2)[CH:42]=[CH:41][CH:40]=1)=[O:44])(=[O:47])=[O:48]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)NS(C)(=O)=O)c2)CN(c2ccccc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)O)C2=O)c1
Yield: 62.2 %

Procedure:
Trifluoroacetic acid (0.32 ml) was added to a solution of 1-(1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea (400 mg) obtained from example 16 in anhydrous 1,2-dichloroethane (10 ml), the mixture was refluxed for 5 hours. Methylene chloride (30 ml) and saturated aqueous sodium bicarbonate were added to the reaction mixture and separated into organic layer and aqueous layer, the aqueous layer was adjusted to pH 2 with 1N hydrochloric acid, and extracted with ethyl acetate. The extraction was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue for trituration and filtrated, to thereby obtain 226 mg of the title compound as a yellow solid (Yield: 64.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:59]=[CH:58][C:54]([CH:55]([OH:57])[CH3:56])=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:57][CH:55]([C:54]2[CH:58]=[CH:59][C:51]([O:50][CH3:49])=[CH:52][CH:53]=2)[CH3:56])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(C)O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (73 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methoxy-α-methylbenzyl alcohol (56 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (74 mg, yield 59%).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1>C(#N)C.CCOC(C)=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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4)cc2OCC3)n(C(C)C)n1
Temperature: 150 °C
Yield: 54.9 %

Procedure:
A microwave vial was charged with a suspension of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (0.239 mg, 0.617 mmol) in 3.0 ml ACN/1.0 mL water. To this suspension was added potassium acetate (182 mg, 1.85 mmol) and 1-methylpyrazole boronic acid pinacol ester (154 mg, 740 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and tetrakis(triphenylphosphine)palladium(0) (57 mg, 56 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 132 mg of 423 (55% theoretical yield). 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.90 (d, J=23.3 Hz, 2H), 7.36 (dd, J=8.4, 1.6 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 5.83 (dt, J=13.3, 6.6 Hz, 1H), 4.51 (s, 4H), 3.87 (s, 3H), 2.25 (s, 3H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[CH2:3][NH:4]C(=O)OC(C)(C)C.ClS([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:27](=[O:28])([O:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])[CH2:3][NH2:4])[NH2:26]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NCC(OC(N)=O)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A solution of 420 mg (1.38 mmol) of the compound of Example 36A in 100 ml of acetonitrile was cooled to −15° C., and a solution of 168 μl (1.93 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise. After 5 min, 50 ml of water were added and the reaction mixture was stirred further at 60° C. overnight. After cooling to RT, 50 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (321 mg, about 90% pure, 85% of theory) corresponded to the title compound and was reacted further without additional purification.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C(NC(C)C)(C)C.C1COCC1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[O:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: Brc1ccco1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of 2-bromofuran (500 mg, 3.402 mmol), Pd(PPh3)2Cl2 (75.69 mg, 0.10784 mmol), CuI (40.17 mg, 0.2109 mmol) and diisopropylamine (0.89 ml, 6.395 mmol) in tetrahydrofuaran (THF) (4 ml) was degassed thoroughly with argon, and trimethylsilyl acetylene (0.648 ml, 4.694 mmol) was added at room temperature. After stirring the reaction mixture for 16 hours at room temperature, it was poured into water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and the solvent was evaporated. The crude material was purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to yield the desired (furan-2-ylethynyl)trimethylsilane (200 mg, 1.21 mmol, yield 35.84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[N:1]1[CH:14]=[N:26][N:25]=[N:24]1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(CC(=O)O)ccc1N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(CC(=O)O)ccc1-n1cnnn1
Temperature: 100 °C

Procedure:
A solution (4-amino-3-methoxyphenyl)acetic acid (1.63 g, 9.006 mmol) and triethyl orthoformate (4.0 g, 27.018 mmol) in 100 mL of HOAc was added sodium azide (644 mg, 9.907 mmol) and heated to 100° C. overnight. The solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated to give [3-methoxy-4-(1H-tetrazol-1-yl)phenyl]acetic acid, which was used for next step without purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[S:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[S:3][C:4]=3[CH:10]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)sc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 74 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-benzothiazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 74% of theory; LC (method 3): tR=2.28 min; Mass spectrum (ESI+): m/z=351 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 7. LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:18]2[CH:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Br:22]C(C(Br)C)C.O>CCCCCC.O1CCCC1>[Br:22][CH2:1][CH2:2][CH2:3][CH2:4][C:17]1([C:19]([OH:21])=[O:20])[C:18]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: [Li]CCCC
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: CC(Br)C(C)Br
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
89 ml (0.11 mol) of a 1.6-Molar n-butyl-lithium solution in hexane are added dropwise to a solution of 21 g (0.1 mol) of 9-fluorenecarboxylic acid in 700 ml of tetrahydrofuran at 0° C. under nitrogen and stirred for one hour. Then, again at 0° C., 13.13 ml (0.11 mol) of dibromobutane are added and the solution is stirred for 30 hours at ambient temperature. After this time 50 ml of water are added and the mixture is stirred for 30 minutes. The solution is concentrated by evaporation, mixed with water and extracted with 250 ml of diethylether. The aqueous phase is acidified with 150 ml of 1N hydrochloric acid and extracted three times with 250 ml of dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent is eliminated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cn1
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.4) (0.2 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure III. Obtained as a yellow solid (0.1 g, 43%). MS (ISP) 463.1 [(M+H)+]; mp 261.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(C)(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)COC(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2-Pyridyl)piperazine (106 m) was dissolved in chloroform (2 mL), and neopentyl chloroformate (0.10 mL) and triethylamine (0.135 mL) were added thereto and stirred at room temperature for 5 hours, and the reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=19/1) to obtain 177 mg of the entitled compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](Br)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:10]1([CH2:9][CH2:8][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCc1ccccc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of aniline (9.1 ml, 100 mmol), phenethylbromide 18.5 g, 100 mmol), potassiumcarbonate (13.8 g, 100 mmol) and 50 ml dimethylsulfoxide is stirred at ambient temperature for 72 hours, and is diluted with 200 ml water. The mixture is extracted three times with diethylether and the combined organic phases is washed with water and brine and dried over magnesium sulphate. The solution is concentrated in vacuo and the crude product is subjected to a vacuum distillation yielding the title compound as a colourless oil dest. 120°-128° C./0.7 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].Cl.[NH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:19])=[C:5]2[OH:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(F)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CNC(=O)C1=C(O)c2cc(F)ccc2C2(CCOCC2)C1=O
Temperature: 95 °C
Reaction time: 13 h
Yield: 17.2 %

Procedure:
A mixture of ethyl 6-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.5 g, 2 mmol), tert-butyl 2-aminoacetate hydrochloride (0.4 g, 2 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.6 g, 5 mmol). The mixture was warmed to 95° C. and stirred for 13 hours, M−1=404. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane and further purified by HPLC to give 0.12 g of the title compound as a pale yellow solid. MS (m/z)=406 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([O:16][CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:19][C@@H:20]([CH3:23])[CH2:21][CH3:22])=[N:11][C:12]=2[NH2:18].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CO>ClCCl>[CH3:17][O:16][C:15]1[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[C:13]([N:14]=1)=[C:12]([NH2:18])[N:11]=[C:10]([O:19][C@@H:20]([CH3:23])[CH2:21][CH3:22])[N:9]=2
Reactant: C1CCNCC1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 9-(5-chloropentyl)-8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-9H-purin-6-amine and piperidine but with purification on silica using a 0-25% methanol in dichloromethane gradient.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:28])[F:27])[CH:4]=1.C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22]([C:39](=[O:41])[CH3:40])[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:27])[F:28])[CH:4]=1
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)n[nH]c2C1
Reaction time: 16 h
Yield: 30.4 %

Procedure:
To a solution of (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (63 mg, 0.15 mmol) and diisopropylethylamine (70 L, 0.40 mmol) in DMF (3.0 mL) was added acetyl chloride (11 μL, 0.15 mmol). The mixture was stirred for 16 hour. The solvent was removed under reduced pressure and the residue was diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with saturated brine (1×20 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% (10% CH3OH in CH2Cl2 with 0.01% NH4OH) in CH2Cl2) and further purified by reverse phase chromatography (Isco CombiFlash Rf unit, 12 g Redisep c18 gold column, 0% to 100% acetonitrile in water) to give 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone as a white solid (20 mg, 94%): mp 176-180° C.; 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.71-7.68 (m, 1H), 7.56-7.49 (m, 2H), 4.94-4.55 (m, 3H), 3.66-3.62 (m, 2H), 3.10 (br s, 2H), 2.85-2.48 (m, 4H), 2.10-2.08 (m, 3H), 1.73 (m, 4H); ESI MS m/z 439 [M+H]+.