Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[NH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>>[CH:32]1([CH2:31][NH:30][C:19]([C:8]2[C:9]3[C:13]([CH3:14])([CH3:15])[O:12][C:11]([CH3:16])([CH3:17])[C:10]=3[S:18][C:7]=2[NH:6][C:4](=[O:5])[C:3]2[C:22]([C:26]([F:28])([F:29])[F:27])=[CH:23][CH:24]=[CH:25][C:2]=2[F:1])=[O:20])[CH2:34][CH2:33]1
Reactant: NCC1CC1
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NCC1CC1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available aminomethylcyclopropane using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 0.15-0.20 (m, 2H), 0.35-0.41 (m, 2H), 0.91-1.01 (m, 1H), 1.46 (s, 6H), 1.48 (s, 6H), 3.03 (dd, J=6.1, 6.0 Hz, 2H), 7.67-7.80 (m, 3H), 8.11 (t, J=5.6 Hz, 1H), 11.56 (br s, 1H). MS (ESI+) m/z 485 (M+H)+.
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH:9]([O:8][CH2:7][CH:6]=[O:13])[C:10]([OH:12])=[O:11]
Reactant: NCCCCCO
Reactant: O=C1COCC(=O)O1
Agent: CS(=O)(=O)[O-]
Product: O=CCOC(NCCCCCO)C(=O)O

Procedure:
methanesulfonate by the following sequence of steps: (a) by reacting diglycolic anhydride and 5-aminopentanol to produce [2-(5-hydroxypentyl)amino-2-oxoethoxylacetic acid, (b) heating to cyclize the latter to obtain 4-(5-hydroxypentyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 5-(3,5-dioxomorpholino)pentyl methanesulfonate and (d) reacting the mesylate with 2-benzhydrylpiperidine.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[N:5][C:6]2[C:7]=1[NH:8][C:9]([CH:12]1[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH2:14][CH2:13]1)=[N:10][CH:11]=2.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:25][CH:17]1[CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][CH2:14][CH2:13][CH:12]1[C:9]1[NH:8][C:7]2=[C:3]([CH3:2])[CH:4]=[N:5][C:6]2=[CH:11][N:10]=1
Reactant: Cc1cnc2cnc(C3CCNC(c4ccccc4)C3)[nH]c1-2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cnc2cnc(C3CCNC(c4ccccc4)C3C)[nH]c1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a 0° C. solution of 7-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (Example 89) (177.3 mg, 0.61 mmol) in THF (10 mL) under a nitrogen atmosphere was added LiHMDS (1.0 M soln from Aldrich Chemical Company) (1.3 mL, 1.27 mmol). This mixture was stirred at 0° C. for 0.5 h then CH3I (Aldrich Chemical Comapny) (41 mL, 0.67 mmol) was added. The 0° C. bath was removed and the solution stirred at room temperature for 2.5 h. The reaction mixture was poured into a separatory funnel containing EtOAc (35 mL) and H2O (50 mL). The organic solution was collected washed with H2O (3×40 mL), saturated NaCl (70 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel 95:5 CHCl3/MeOH as eluant to give 164 mg (86%) of the title compound as a beige colored solid. Mp: 123.0-125.0° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.68 (m, 2), 1.78 (m, 4), 2.30 (s, 3), 3.42 (br s, 4), 3.66 (s, 3), 7.44-7.54 (m, 5), 8.61 (s, 1) MS m/z: 307 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:4]([CH:3]=1)[C:10]([OH:9])=[O:11]
Reactant: O=C1OCc2ncc(Cl)cc21
Reactant: Oc1ccc(F)cc1
Product: O=C(O)c1cc(Cl)cnc1COc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 3-chlorofuro[3,4-b]pyridin-5 (7H)-one (step 1 of Example 18) and 4-fluorophenol:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:13][CH2:12][N:11]3[C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:23]([S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH:22]=4)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]3[CH2:9]2)[CH2:3][CH2:2]1.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[C:60]([CH:65]=O)=[CH:61][CH:62]=[CH:63][CH:64]=2)=[CH:55][CH:54]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH2:65][N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([N:8]3[CH2:13][CH2:12][N:11]4[C:14]([NH:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH2:29][CH2:30][N:31]6[CH2:32][CH2:33][O:34][CH2:35][CH2:36]6)=[C:23]([S:45]([C:48]([F:49])([F:50])[F:51])(=[O:47])=[O:46])[CH:22]=5)(=[O:19])=[O:20])=[N:15][N:16]=[C:10]4[CH2:9]3)[CH2:3][CH2:2]2)=[CH:57][CH:58]=1
Reactant: O=S(=O)(Nc1nnc2n1CCN(C1CCCNCC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=S(=O)(Nc1nnc2n1CCN(C1CCCN(Cc3ccccc3-c3ccc(Cl)cc3)CC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a vial containing N-(7-azepan-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide (62 mg, 0.080 mmol) and 4′-chloro-biphenyl-2-carbaldehyde (52.1 mg, 0.241 mmol) was added methanol (2.5 mL) under nitrogen. The reaction was stirred in an ice bath for 10 minutes and then acetic acid (5.51 μL, 0.096 mmol) was added. After stirring in the ice bath for an additional 15 minutes, sodium cyanoborohydride (40.3 mg, 0.642 mmol) was added. The reaction was then allowed to warm to ambient temperature and stir for 72 hours. The reaction mixture was concentrated, filtered and purified via flash chromatography on silica gel (10-50% methanol in CH2Cl2) to afford the title compound (50 mg, 64% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24]([N:27](CC3C=CC(OC)=CC=3)[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:26])=[O:25])[CH:22]=[CH:23][C:14]1=2)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:25])=[O:26])[CH:22]=[CH:23][C:14]1=2)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(C)N3c2ccc(C(F)(F)F)cc2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1COc2cc(S(=O)(=O)Nc3nccs3)ccc2N1c1ccc(C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (790 mg, 1.31 mmol) in dichloromethane (20 mL) was added TFA (2.0 mL, Spectrochem) at 0° C. and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to get the crude material which was basified (pH˜9) with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude material which was purified by column chromatography (silica gel 100-200 mesh, elution 0-5% methanol in dichloromethane) to obtain 4-(2-cyano-4-(trifluoromethyl)phenyl)-3-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (530 mg, 84%) as off white solid. 1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 8.44 (s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.27-7.22 (m, 2H), 7.19 (d, J=8.5 Hz, 1H), 6.82 (d, J=4.5 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 4.28-4.03 (m, 3H), 1.20 (d, J=6.5 Hz, 3H); MS (ESI, positive ion) m/z 481.1 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:22])[CH2:20][CH3:21].CO[C:26](=O)[C:27]1C=C(SC2C=CC=CC=2N)C=C[C:28]=1NC(=O)CC>>[C:19]([NH:18][C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:26][CH2:27][CH3:28])=[CH:9][C:4]=1[C:3]([OH:2])=[O:23])(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Nc1ccc(Sc2ccccc2N)cc1C(=O)OC
Reactant: CCC(=O)Nc1ccc(Oc2ccccc2N)cc1C(=O)OC
Product: CCCNc1ccccc1Oc1ccc(NC(=O)CC)c(C(=O)O)c1

Procedure:
The following compounds were obtained by reacting the intermediate 2-propionylamino-5-(2-amino-phenoxy)-benzoic methyl ester or 5-(2-amino-phenylsulfanyl)-2-propionylamino-benzoic acid methyl ester (EXAMPLE 17) with boronic acids according to EXAMPLE 6 or with aldehydes as described above.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2ccc(Br)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A solution of 4-bromo-2-fluoro-benzoyl chloride (2 g, 8.42 mmol) in dichloromethane (10.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (1.0 g, 8.42 mmol), pyridine (2.0 mL, 25.27 mmol) and dichloromethane (40.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as an off-white solid. ESI-MS m/z calc. 323.99, found 325.1 (M+1)+; Retention time: 1.37 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m, 1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=O.[H-].[Na+].ClCC[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])[CH2:28][CH2:27]1.O>CN(C=O)C>[CH3:39][O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:2][CH2:3][NH:5][C:6]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:7]=2[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: Cc1cccc(C(=O)N(C)C)c1NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCNc2c(C)cccc2C(=O)N(C)C)CC1
Temperature: 50 °C
Yield: 11.3 %

Procedure:
A mixture of 2-trifluoroacetylamino-N,N,3-trimethylbenzamide (584.2 mg, 2.13 mmol), prepared as in Example 22, and sodium hydride (110 mg, 2.7 mmol) in 10 mL of DMF was heated at 50° C. for 20 minutes and then 1-chloro-3-[4-(2-methoxyphenyl)piperazin-1-yl]propane (647 mg, 2.13 mmol) was added. The mixture was heated at 80° C. for 18 hours, then poured into water and extracted with ethyl acetate (3×50 mL). The combined extract was washed with saline, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with 6% methanol/methylene chloride to give 2-{3-[4-(2-methoxy-phenyl)piperazin-1-yl]propylamino}-N,N,3-trimethylbenzamide (100 mg, 0.24 mmol).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Cl.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCC(F)(F)F)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 2,2,2-trifluoroethanamine hydrochloride (28 mg, 0.208 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (43 mg, 0.378 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 60 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 3.57 (s, 2H), 4.10-4.18 (m, 2H), 7.17 (t, J=74.7 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H), 7.39-7.48 (m, 2H), 7.60-7.66 (m, 1H), 7.84 (d, J=15.6 Hz, 1H), 8.00 (s, 1H), 8.85 (br s, 1H); ESI-MS (m/z) 504.22 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([I:23])=[CH:18][C:17]=3[Cl:24])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.[CH3:27][O-:28].[Na+]>CO.O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([I:23])=[CH:18][C:17]=3[Cl:24])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([O:28][CH3:27])[N:11]=[CH:10][CH:9]=3
Reactant: Clc1cc(I)cc(Cl)c1Nc1nc2ccc(Br)cc2c2c(Cl)nccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccc(Br)cc3c12
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-1-chloro-N-(2,6-dichloro-4-iodophenyl)benzo[c]-2,6-naphthyridin-5-amine (1.56 g, 2.69 mmol) in methanol (30 mL) was added sodium methoxide (10 mL, 25% in methanol) and heated the reaction to 100° C. for 45min. The reaction was cooled to room temperature and a few drops of water were added to quench the reaction. The organic layer was evaporated under vacuum and the residue was diluted with ethyl acetate and extracted with water. The organic layer was separated, dried with sodium sulfate, filtered and evaporated. The residue was taken to the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[N:20]=[CH:19][S:18][C:14]=2[N:15]=[CH:16][N:17]=1.F[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.[H-].[Na+]>CN(C=O)C.O.Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:21][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[N:20]=[CH:19][S:18][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Cc1cc(O)ccc1OCCNc1ncnc2scnc12
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(C(F)(F)F)ccn2)ccc1OCCNc1ncnc2scnc12
Reaction time: 2 h
Yield: 104 %

Procedure:
3-Methyl-4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethoxy]-phenol (0.13 g, 0.43 mmol) and 2-fluoro-4-trifluoromethylpyridine (0.1 g, 0.6 mmol) were dissolved with magnetic stirring in DMF (4 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. To the solution was added NaH (60% dispersion in oil; 60 mg, 1.5 mmol) and the reaction mixture was stirred for 2 h. The reaction was diluted with H2O (100 mL), and 2 N HCl was added to adjust the pH to 6. After 24 h, a pale brown film had formed on the flask wall. The aqueous supernatant was extracted with Et2O (2×50 mL), and the pooled aqueous fractions were combined with the brown film, and then concentrated in vacuo to yield 0.2 g of a tan semi-solid. Recrystallization from hexane afforded {2-[2-methyl-4-(4-trifluoromethylpyridin-2-yloxy)-phenoxy]-ethyl}-thiazolo[5,4-d]pyrimidin-7-ylamine (Compound 9; 70 mg) as white crystals: mp 107-111° C.; 1H NMR (600 MHz, CDCl3) δ 8.78 (s, 1H), 8.53 (s, 1H), 8.29 (d, J=5.2 Hz, 1H), 7.17-7.11 (m, 1H), 7.08 (s, 1H), 6.92-6.90 (m, 2H), 6.85 (d, J=8.7 Hz, 1H), 6.56 (s, 1H), 4.29-4.20 (m, 2H), 4.11 (d, J=4.4 Hz, 2H), 2.25 (s, 3H); ESIMS m/z 448.1 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@H:10]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of (4S)-1-(tert-butyloxycarbonyl)-4-hydroxy-L-proline tert-butyl ester (313 mg, 1.09 mmol) in pyridine (2.0 mL) cooled to 0° C. was added methanesulfonyl chloride (0.17 mL, 2.18 mmol). The reaction mixture was allowed to reach room temperature, and after 2 hours was diluted with ethyl acetate (100 mL), washed with saturated sodium hydrogencarbonate solution, 1 M citric acid, water, dried (Na2 SO4), and evaporated. The crude product was purified by flash silica gel chromatography eluting with 15% acetone/hexane; yield 251 mg (52% over 2 steps). 400 MHz 1H NMR (CDCl3): δ1.42-1.48 (3s, 18H); 2.38-2.50 (m, 2H); 2.99 (2s, 3H); 3.69-3.79 (m, 2H); 5.22 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.C1(C)C=CC=CC=1>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:20][CH3:21])([CH3:18])[CH3:19]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]ncc12
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Yield: 73.2 %

Procedure:
1.46 g (4.746 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is stirred with 632 mg (4.746 mmol) of 4-aminoindazole in 6.78 ml of glacial acetic acid for two days at room temperature. The reaction mixture is drawn off three times with toluene in a rotary evaporator, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 1.47 g (73.5%) of the desired compound is isolated.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.C(O)(=O)C.[CH3:9][C:10]1([CH3:22])[O:14][C:13]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=2[O:11]1>O>[CH3:9][C:10]1([CH3:22])[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([N+:1]([O-:4])=[O:3])=[CH:15][C:13]=2[O:14]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2O1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2O1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A solution of 90% (fuming) nitric acid (22 ml) and glacial acetic acid (11 ml) cooled at 12° C. was treated in portions with solid compound from Example 3B (5.4 g, 27.7 mmoles) so as to maintain the temperature of <17° C. After the addition, stirring was continued for 15 minutes, when the internal temperature began to fall. The mixture was diluted to 100 ml with water, the yellow solid filtered, washed with water, taken up in CH2Cl2, dried (Na2SO4) and evaporated to give 5.43 g (82%) of pure title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)=[N:15][CH:16]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Product: Cc1ccc2ccnc(Nc3ccc(Cl)cn3)c2n1

Procedure:
The title compound, MS: m/e=271.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-amino-5-chloropyridine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:1][C:2]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCOc1ccc(C(=O)OC)c(O)c1
Product: COCCOc1ccc(C(=O)OC)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 89.6 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 2-hydroxy-4-(2-methoxyethoxy)benzoate (2.72 g, 12.02 mmol) is alkylated with 1-tert-butoxycarbonyl-4-hydroxy-piperidine (2.44 g, 12.02 mmol) to afford methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-methoxyethoxy)benzoate (4.41 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2(Cl)[CH2:15][CH2:14]2)=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:17]C1(C2C=C(C(OCC)=O)N(C)N=2)CC1.ClN1C(=O)CCC1=O>>[Cl:1][C:2]1[C:3]([C:13]2([F:17])[CH2:15][CH2:14]2)=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(Cl)c(C2(Cl)CC2)nn1C
Reactant: CCOC(=O)c1cc(C2(F)CC2)nn1C
Agent: O=C1CCC(=O)N1Cl
Product: CCOC(=O)c1c(Cl)c(C2(F)CC2)nn1C

Procedure:
The preparation was carried out analogously to the preparation of ethyl 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate using ethyl 3-(1-fluorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate and 3 eq of N-chlorosuccinimide