Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH3:13])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:14](O)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:14]([O:12][CH2:11][C@H:9]1[O:10][C@H:2]([O:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCC(=O)O
Product: CCCCCCCC(=O)OC[C@H]1O[C@H](OC)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 36 h
Yield: 33.4 %

Procedure:
Methyl α-D-glucopyranoside (20.0 g, 0.10 mol, prepared according to Example 6), was esterified with octanoic acid (29.7 g, 0.21 mol) by the procedure described in Example 1 using 6.0 g of an immobilized lipase (from Candida antarctica) as a catalyst. After 36 hours HPLC analysis showed 77% conversion (65% monoester, 12% diester). The reaction was stopped by filtering off the enzyme. Part of the crude product was purified by chromatography yielding 10.7 g (32.4%) of the title compound which was identified by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[C:20]([CH:24]=1)[C:21](O)=[O:22])(=[O:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:21]([C:20]1[CH:24]=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=[CH:18][C:19]=1[O:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])=[O:22])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): MS (m/e): 462.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[C:4]([CH2:18]C)[CH:3]=1.Br[C:21]1C=C(C)C(CCO)=C(C)C=1.C([Si](Cl)(C)C)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])=[C:16]([CH3:21])[CH:17]=1
Reactant: Cc1cc(Br)cc(C)c1CCO
Reactant: CCc1cc(Br)ccc1CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Product: Cc1cc(Br)cc(C)c1CCO[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
Using a procedure analogous to that used to prepare 46A, 32B (3.0 g, 13.1 mmol) was reacted tert-butylchlorodimethylsilane to afford 50A (3.58 g, 80%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm −0.01 (s, 9 H) 2.30 (s, 6 H) 2.84 (t, J=7.70 Hz, 2 H) 3.66 (t, J=7.70 Hz, 2 H) 7.13 (s, 2 H).
Reaction SMILES: C([O:5][P:6]([O:41]C(C)(C)C)([O:8][CH:9]([O:11][C:12](=[O:40])[N:13]([C:37](=[O:39])[CH3:38])[CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:34][C:33]4[C:29](=[N:30][N:31]([CH3:35])[CH:32]=4)[CH2:28]3)=[C:23]([F:36])[CH:22]=2)[CH2:16]1)[CH3:10])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[P:6]([O:8][CH:9]([O:11][C:12](=[O:40])[N:13]([C:37](=[O:39])[CH3:38])[CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:34][C:33]4[C:29](=[N:30][N:31]([CH3:35])[CH:32]=4)[CH2:28]3)=[C:23]([F:36])[CH:22]=2)[CH2:16]1)[CH3:10])([OH:7])([OH:41])=[O:5]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)OP(=O)(OC(C)(C)C)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OC(C)OP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 17b (1 equiv) in dichloromethane is added TFA (3 equiv) and the reaction mixture is stirred at rt for 3 h. The reaction mixture is concentrated in vacuo, and purified directly by HPLC (C-18 column, 10-100% gradient elution, MeCN:H2O) to give the title compound. Theoretical MS 542 (M+1)+
Reaction SMILES: C(OC([N:8]1[C@H:14]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:11]1[C:10]2([CH2:13][C@@H:14]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[NH:8][CH2:9]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1CNc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NC[C@@H]2CC3(CC3)CN2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl6-(((5-chloropyridin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylate Intermediate 60, 600 mg, 1.77 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C., then trifluoroacetic acid (4 ml) was added. After 1 hour at 0° C. and 3 hours at room temperature the solution was evaporated, the residue re-dissolved in dichloromethane was washed with saturated NaHCO3 aqueous solution. The organic layers were dried (Na2SO4) and concentrated under vacuum. The crude was purified by silica gel column chromatography (CHCl3/MeOH=8/2). (S)—N-(5-azaspiro[2.4]heptan-6-ylmethyl)-5-chloropyridin-2-amine was obtained as light yellow oil (400 mg).
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([N:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([N:34]([CH3:36])[CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 14 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 25 (14% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.64 and 2.69 (d, 6H), 2.85 and 3.09 (2t, 2H), 3.59 and 4.20 (2t, 2H), 3.92 (s, 3H), 4.49 and 5.09 (2s, 2H), 6.33 and 6.82 (2d, 1H), 6.96 and 7.15 (2d, 1H), 7.03-7.07 (m, 2H), 7.50-7.60 (m, 1H), 7.86-8.01 (m, 2H), 8.08-8.12 (m, 1H), 8.57-8.63 (m, 2H); MS (ESI) m/z 455 ([M+H]+).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[N:16]([CH2:18][CH2:19][O:20][CH3:21])[CH3:17].Cl>C(O)C>[CH3:21][O:20][CH2:19][CH2:18][N:16]([CH3:17])[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:2]=[O:1])[CH:8]=2)[NH:12][N:11]=1
Reactant: COCCN(C)c1n[nH]c2ccc(C3OCCCO3)cc12
Agent: Cl
Solvent: CCO
Product: COCCN(C)c1n[nH]c2ccc(C=O)cc12
Temperature: 90 °C

Procedure:
To a solution of 170 mg (0.583 mmol) 5-(1,3-dioxan-2-yl)-N-(2-methoxyethyl)-N-methyl-1H-indazol-3-amine (Example 47A) in ethanol (10 ml) were added 1.9 ml (5.83 mmol) 3 M hydrochloric acid, and the solution was heated to 90° C. for 30 min. After cooling, the mixture was concentrated under reduced pressure. The remaining material (135 mg, 99% of th.) was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Cl:10])=[C:4]([O:11][CH3:12])[CH:3]=1.ClCCCl.[C:17](Cl)(Cl)=[S:18].C(=O)([O-])[O-].[Ca+2]>O>[Cl:10][C:5]1[CH:6]=[C:7]([C:2]([N:1]=[C:17]=[S:18])=[CH:3][C:4]=1[O:11][CH3:12])[C:8]#[N:9]
Reactant: COc1cc(N)c(C#N)cc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCCl
Solvent: O
Product: COc1cc(N=C=S)c(C#N)cc1Cl
Temperature: 20 °C

Procedure:
To a solution of 27.4 g. (0.15 mole) of 6-amino-3-chloro-4-methoxybenzonitrile in 150 ml. of 1,2-dichloro-ethane at 0°-5° C. is added with stirring a mixture of 23 g. (0.2 mole) thiophosgene, 100 ml. 1,2-dichloroethane, 20 g. (0.2 mole) calcium carbonate and 200 ml. of water. After the addition the mixture is stirred for one hour at 0°-5° C., warmed to 20° C. and stirred for 6 hours at this temperature and finally at 35° C. for an hour. The reaction mixture is filtered and the organic layer separated, washed with dilute hydrochloric acid, water and dried (MgSO4). The solvent is removed by evaporation and the residue used without purification in the next step.
Reaction SMILES: [F:1][C:2]([F:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15](O)=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15]([NH:56][CH2:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-c2cn(CC(F)(F)c3ccccc3)nn2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn(CC(F)(F)c3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1-(2,2-difluoro-2-phenylethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid (0.10 g, 0.28 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.07 g, 0.34 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.51 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroxy-benzotriazole (0.10 g, 0.74 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and 3-(aminomethyl)pyridine (0.04 mL, 0.04 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, then diluted with ethyl acetate (30 mL), washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to the title compound as a white solid (0.03 g, 7%): mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.53-8.47 (m, 1H), 8.23 (s, 1H), 7.74-7.64 (m, 1H), 7.55-7.39 (m, 5H), 7.32-7.22 (m, 1H), 6.56 (t, J=5.6 Hz, 1H), 5.02-4.93 (m, 2H), 4.60 (d, J=5.6 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.8, 157.6, 157.3, 149.2, 149.1, 143.1, 135.7, 133.7, 132.8, 131.2, 129.0, 125.0, 124.6, 123.7, 122.9, 118.6, 56.1, 41.6, 17.3; MS (ES+) m/z 441.4 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32](Cl)[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 85 °C
Yield: 83.3 %

Procedure:
To a 50 mL pear flask were added tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (0.85 g, 2.37 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.638 g, 3.78 mmol) in DMSO (12 mL). Triethylamine (1.65 mL, 11.8 mmol) was added to the mixture which was then heated to 85° C. for three hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, 25-100% EtOAc/heptane gradient) to give the title compound as an off-white solid (0.97 g, 83%). ESI-MS m/z [M+H]+ calc'd for C25H33N9O2, 492. found 492.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:15]3[C:25](=[O:26])[NH:24][CH:23]=[CH:22][C:16]=3[N:17]=[C:18](SC)[N:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[NH2:36]>>[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[NH:36][C:18]1[N:19]=[C:14]([NH:13][C:5]2[CH:4]=[C:3]([C:2]([F:28])([F:27])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[C:15]2[C:25](=[O:26])[NH:24][CH:23]=[CH:22][C:16]=2[N:17]=1
Reactant: CSc1nc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1
Reactant: N[C@@H]1CCCC[C@H]1N
Product: N[C@@H]1CCCC[C@H]1Nc1nc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1

Procedure:
The title compound was prepared as described in Example 1g by starting from 4-(3,5-bis(trifluoromethyl)phenylamino)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (100 mg, 0.24 mmol) and (±)-trans-1,2-diamino cyclohexane and continuing until the reaction yielded the title compound, 2-((1R,2R)-2-aminocyclohexylamino)-4-(3,5-bis(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one. MS m/z: 487 (M+1)+ 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.97 (m, 10H), 6.10 (d, J=7.2 Hz, 1H), 7.41-7.44 (m, 3H), 7.41-7.76 (m, 4H), 8.47 (s, 2H), 12.49 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCOCC1.[C].[Pd]>[NH2:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1N1CCCC1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cnccc1N1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
4-pyrrolidine-1-yl-3-nitropyridine (2.10 g, 10.9 mmol) was dissolved in 40 ml of 1,4-dioxane. After the atmosphere was replaced with nitrogen, 0.42 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtration and the filtered cake was washed with 1,4-dioxane. The filtrate and the washings were combined and then concentrated to obtain 1.61 g of a brown liquid (yield: 90.7%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[N:10]([CH2:13][CH2:14][CH2:15][NH2:16])=[N+:11]=[N-:12]>>[N:10]([CH2:13][CH2:14][CH2:15][NH:16][C:2]1[N:4]=[C:5]([NH:16][CH2:15][CH2:14][CH2:13][N:10]=[N+:11]=[N-:12])[N:7]=[C:8]([NH:16][CH2:15][CH2:14][CH2:13][N:10]=[N+:11]=[N-:12])[N:1]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NCCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: [N-]=[N+]=NCCCNc1nc(NCCCN=[N+]=[N-])nc(NCCCN=[N+]=[N-])n1

Procedure:
FIG. 6 is a series of schemes showing the synthesis of the monomers used in the adhesives test. The first reaction to make 1 is an N-sulfonylation of the nitrogen mustard, N,N-di(2-chloroethyl) amine, followed by an SN2 displacement of the chlorides to obtain the diazide, 1. The second reaction is an N-propargylation of 4-methyl-benzenesulfonamide under mild conditions to give the diacetylene, 2. The last reaction is the displacement of the chlorides of cyanuric chloride with 3-azidopropylamine to give the triamino-1,3,5-triazine 5.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C[C@H](c1ccccc1)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@H](CC(=O)O)c4ccccc4)cc3)ccc2C(C)(C)C)c1
Reaction time: 21 h
Yield: 71.5 %

Procedure:
To a stirred solution of 42.3 (0.048 g, 0.09 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 21 hours and then concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 42 (33 mg, 73% yield) as a colorless oil. MS ESI (neg.) m/e: 511.3 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:16]=[N:15]2)[N:3]=1
Reactant: C#CCCn1cc(-c2ccccc2C)cn1
Reactant: FCc1cccc(Br)n1
Product: Cc1ccccc1-c1cnn(CCC#Cc2cccc(CF)n2)c1
Yield: 30 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.26 mmol) and 1-but-3-ynyl-4-o-tolyl-1H-pyrazole (50 mg, 0.24 mmol, Example 142(A)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (72 μmol, 30%) of 2-(fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid with a purity of 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29]Br)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][NH:14][CH:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=4[N:6]=3)[CH2:10]2)[CH:22]=1
Reactant: COC(=O)Cc1cccc(OCCBr)c1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1cccc(OCCNC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamine (190 mg), [3-(2-bromoethoxy)phenyl]acetic acid methyl ester (205 mg) and potassium carbonate (114 mg) was stirred at 80° C. for 2 hours. To the reaction solution, was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (174 mg). Yield: 52%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:17]3[CH:16]=[N:15][C:14]([NH2:28])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 87 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (4.2711 g, 10.0 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2CO3 (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3J2CI2 (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc) to afford 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4167 g, 65% yield, −95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[N+:22]([O-])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[C].[Pd].C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[NH2:22])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc([N+](=O)[O-])c(NCCC2CCC3(CC2)OCCO3)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(NCCC2CCC3(CC2)OCCO3)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To 45 mL of an ethanol solution containing 0.8 g of N-(2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl)-5-methoxy-2-nitroaniline, 0.25 g of 10% palladium-carbon was added at room temperature, and the mixture was stirred at 40° C. for 3 hours and 30 minutes under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure to obtain 0.81 g of a violet oily substance, 2-(2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl)amino-4-methoxyaniline.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(#N)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:16][CH2:17][N:12]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1ccc(C2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(C2CCN(Cc3nc4cccnc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 38A (50 mg, 0.11 mmol), 2-(4-piperidinyl)pyridine (25 mg, 0.13 mmol), and DIEA (340 μL, 2.1 mmol) were combined in acetonitrile (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.13 (m, 4H), 3.13 (m, 4H), 3.61 (m, 3H), 7.38 (d, J=4.75 Hz, 1H), 7.76(dd, J=8.3 Hz, 4.6 Hz, 1H), 7.91 (m, 1H), 8.31 (m, 1H), 8.54 (m, 2H), 8.72 (dd, J=4.6 hz, 1.53 Hz, 1H); (ESI) m/z 311 (M+H)+.
Reaction SMILES: Br[CH:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:15].[H-].[Na+].Cl>CS(C)=O>[CH3:16][CH:2]1[CH2:3][CH2:4][C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=2[O:15]1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1CCC(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c2c1CCC(C)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
40.5 g of 1C was added in portions over 20 minutes to a stirred mixture of 3.4 g of sodium hydride in 300 ml of DMSO at room temperature, and the resulting mixture was stirred for 18 hours at room temperature. The mixture was poured into ice water, made slightly acidic with concentrated hydrochloric acid and filtered. The solid was dried to give 3,4-dihydro-2,5-dimethyl-8-nitro-2H-1-benzopyran (1D) as a yellow solid, m.p.: 83°-85° C.