Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC>[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[C@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of CuBr.SMe2 (3 g, 14.6 mmol) in anhydrous ether (100 ml) under an argon atmosphere at −78° C., was added methyl lithium (1.6M in ether, 16.5 ml, 4.0 eq, 26.5 mmol) dropwise and the solution allowed to warm to room temperature over 1 h. The mixture was recooled to −78° C., and a solution of (S)-2-(trityl-amino)-butyraldehyde (2.2 g, 6.62 mmol) in ether (25 ml) was added dropwise with stiffing. The reaction mixture was stirred at this temperature for 2 h then allowed to warm to room temperature over 1 h. A saturated aqueous solution of NH4Cl (50 ml) was added and the two layers separated. The organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel column chromatography, eluted with hexane:ethyl acetate (80:20) to afford (2R,3S)-3-(trityl-amino)-pentan-2-ol as a light yellow oil; Yield: 1.5 g (66%). (75% de 2R, 3S: 25% de 2S, 3S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.0.47+0.55 (2×t, J=7.50+7.26 Hz —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5 H, —NHCH(CH2CH3)CH(CH3)OH), 2.01 (1 H, m, —NHCH(CH2CH3)CH(CH3)OH), 3.22-3.43 (m, 1H, —NHCH(CH2CH3) CH(CH3)OH), 4.41 [1 H, d, J=3.3, NHCH(CH2CH3)CH(CH3)OH], 7.14-7.56 (15 H, m, ArH). δC (250 MHz, CDCl3) 146.88 (C), 128.97 (6×CH), 127.83 (6×CH), 126.43 (3×CH), 71.03 (C), 68.13 (CH), 58.77 (CH), 23.09 (CH2), 17.88 (CH3), 10.47 (CH3)
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:18]2[CH:19]=[N:20][C:21]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=2[C:24]#[N:25])=[CH:13][C:12]=1[C:30](=[O:40])[N:31]([CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:17][C:15]1[C:14]([C:18]2[CH:19]=[N:20][C:21]([C:26]([F:29])([F:27])[F:28])=[CH:22][C:23]=2[C:24]#[N:25])=[CH:13][C:12]([C:30](=[O:40])[N:31]([CH3:39])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[C:11]([CH:16]=1)[O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:41])=[O:5]
Reactant: Cc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)O
Yield: 16.7 %

Procedure:
4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acid tert-butyl ester (410 mg, 0.7 mmol) was stirred in a mixture of trifluoroacetic acid in DCM (1/1, 3 mL) for 2 hrs. Concentration followed by purification by HPLC gave 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acid 20-1 (62 mg). MS: 532.6 (M+H)+; tR=5.29 min (method 3). NMR (CDCl3, reported as the major isomer of cis-trans amide rotamers), δ, 8.54 (1H, s), 7.94 (1H, s), 7.34-7.25 (1H, m), 7.18-7.14 (2H, m), 7.14-7.04 (1H, m), 7.02 (1H, s), 6.92 (1H, s), 4.08 (2H, t, J=6.3 Hz), 3.40 (3H, s), 2.62 (2H, t, J=6.3 Hz), 2.30-2.18 (2H, m), 2.57 (3H, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH2:14][CH2:13]1.N1C=CN=C1.[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[Si:33]([O:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[N:12]1[CH2:13][CH2:14][CH:15]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH2:16][CH2:17]1)([C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)C1CCN(C2Cc3ccccc3CC2O)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C2Cc3ccccc3CC2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 22 (400 mg, 1.25 mmol) and imidazole (400 mg) in CH2Cl2 (50 mL), TBDMSCl (2.5 mmol) was added. The reaction mixture was stirred overnight at room temperature until TLC indicated that the reaction was complete. The reaction mixture was washed by brine and 1M NaH2PO4 (30 mL×3). The organic layer was dried and concentrated to a residue. The crude product was purified with column chromatography to afforded 23 (400 mg, 70%). 1H NMR (CDCl3,): δ 0.12 (s, 6H), 0.91 (s, 9H), 1.65-1.77 (m, 4H), 2.46-3.05 (m, 9H), 3.17 (s, 3H), 3.69 (s, 3H), 4.13 (br, 2H), 7.04-7.12 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:16][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1cc(C(=O)c2ncccn2)oc1C
Solvent: CO
Product: Cc1cc(O)c(-c2ncccn2)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(2-pyrimidyl)-methanone (220 mg), methanol (2 ml), and a 28% aqueous ammonia solution (2 ml) were placed in a sealed tube, and the mixture was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give 5,6-dimethyl-2-pyrimidin-2-yl-pyridin-3-ol (129 mg, yield 59%).
Reaction SMILES: [N:1]1[C:9]([S:10]CC2OC(=O)C3C(C=2C2C=CC=CC=2)=CC=CC=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.Br[CH:30]([C:32]1[O:33][C:34](=[O:49])[C:35]2[C:40]([C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:31].O.N1C(S)=C2C(NC=N2)=NC=1.C([O-])([O-])=O.[K+].[K+]>>[N:1]1[C:9]([S:10][CH:30]([C:32]2[O:33][C:34](=[O:49])[C:35]3[C:40]([C:41]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:31])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: Sc1ncnc2[nH]cnc12
Agent: [K+]
Solvent: O
Product: CC(Sc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Yield: 63 %

Procedure:
The title compound was made in a similar way as that of the compound of example 10, 3-(1-bromoethyl)-4-(3-fluorophenyl)-1H-isochromen-1-one (intermediate C6, 70 mg, 0.202 mmol), 9H-purine-6-thiol hydrate (34.3 mg, 0.202 mmol) and K2CO3 (27.9 mg, 0.202 mmol). The resulting mixture was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (53 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]2[CH:21]=[CH:20][C:19](F)=[C:18](F)[CH:17]=2)=[N:6][CH:7]=1.Cl.[C:25]([O:29]C(N1CCCC(C2C=CC(OC)=CC=2)C1)=O)(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]2[CH:21]=[CH:20][C:19]([O:29][CH3:25])=[CH:18][CH:17]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(C2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Fc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1F
Agent: Cl
Product: COc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-Chloro-2-[(3SR,4SR)-3-(3,4-difluoro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride the title compound was prepared from 445-Chloro-pyridin-2-yloxymethyl)-3-(4-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as off-white foam (1:1 mixture cis:trans). MS (m/e): 333.4 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[CH2:3][N:4]([CH:9]([C:13]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=1)[CH:10]([CH3:12])[CH3:11])[C:5](=[O:8])[CH:6]=[CH2:7].C(OC(=O)NC(C)(C)C(C(=O)C=C)(C(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)N)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:22]1[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=[C:13]1[CH:9]([N:4]1[C:5](=[O:8])[CH2:6][CH2:7][NH:1][C:2]([CH3:32])([CH3:33])[CH2:3]1)[CH:10]([CH3:12])[CH3:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)N(CC(C)(C)N)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)C(N)(C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)C(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CC(C)(C)NCCC1=O

Procedure:
N-(2-Amino-2-methyl-propyl)—N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl propyl]-acrylamide: According to the procedure of Example 1d above, ({acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester (730 mg, 1.29 mmol) was treated with 50% TFA in CH2Cl2 (10 mL) to give the title compound: MS (ES) m/e 467.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH3:20])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[Cl-].[Na+].O.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([CH3:20])=[CH:15][N:14]=2)[CH:7]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: OB(O)c1cc(Cl)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(-c2cc(Cl)ccc2F)nc1N
Temperature: 25 °C

Procedure:
trans-Dichlorobis(triphenylphosphine)palladium (II) (1.179 g, 1.680 mmol), 5-chloro-2-fluorophenylboronic acid (6.15 g, 35.3 mmol), 2-chloro-5-methylpyrimidin-4-amine (2.411 g, 16.80 mmol), were combined with 2M Na2CO3 (8.40 ml, 16.80 mmol) in dioxane (79 mL) and then heated at reflux for 1 hour. The reaction mixture was then cooled to room temperature and concentrated on a rotovap to afford a tan solid. The solid was suspended in brine (50 mL) and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated on a rotovap to afford an amber colored oil which was loaded onto silica (12 g) and purified by silica chromatography using a step gradient eluted with (10-75% ethyl acetate/hexanes) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (3H, d, J=0.76 Hz) 6.85 (2H, br. s.) 7.31 (1H, dd, J=10.61, 8.84 Hz) 7.46-7.55 (1H, m) 7.88 (1H, dd, J=6.57, 3.03 Hz) 8.06 (1H, d, J=0.76 Hz). ESI-MS: m/z 238.1 (M+H).
Reaction SMILES: [ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[CH:22]=1>>[ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[CH:22]=3)([OH:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CC1CC(CCC2CCCC2)CCC1=O
Reactant: CCOc1cccc(Br)c1
Agent: Cl
Product: CCOc1cccc(C2(O)CCC(CCC3CCCC3)CC2CN(C)C)c1
Yield: 52 %

Procedure:
The base of compound (56) was reacted with 1-bromo-3-ethoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with diisopropyl ether via a silica gel column and was taken up in 2-butanone/ether. After adding trimethylchlorosilane/water, compound (58) was obtained in a yield of 52% theoretical.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][C@@H:30]1[C@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[NH:31]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:31]4[C@H:30]([CH3:29])[C@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:33][C:32]4=[O:41])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4C(=O)O[C@@H](c5ccccc5)[C@H]4C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[F:33][C:34]([F:40])([F:39])[S:35](Cl)(=[O:37])=[O:36]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:35]([C:34]([F:40])([F:39])[F:33])(=[O:37])=[O:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)nc1N

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and trifluoromethanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-trifluoromethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 478.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)=[N:10][CH:9]=2)[CH:7]=1.[H-].[Na+].Br[CH2:32][CH2:33][OH:34]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:17]=[N:16][N:15]([CH2:32][CH2:33][OH:34])[CH:14]=3)=[N:10][CH:9]=2)[CH:5]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=2)[CH:3]=1
Reactant: OCCBr
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(-c3cn[nH]c3)s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(-c3cnn(CCO)c3)s2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
To a sealed tube was added N-{3-methyl-5-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine (38.0 mg, 0.095 mmol), DMF (950 μL, 0.1 M) and NaH (15.0 mg, 0.380 mmol, 60% wt). The reaction was allowed to age for 20 minutes. Next was added 2-bromo ethanol (11.8 mg, 0.095 mmol) and the reaction was allowed to stir at rt for 4 hours. The completed reaction was quenched with H2O (100 μL) and was concentrated in vacuo. Purification by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v formic acid modifier) to afford the title product (2.8 mg, 0.0057 mmol, 6.0%). MS ESI: [M+H]+ m/z 447.1. 1H NMR (600 MHz, DMSO) δ 10.24 (s, 1H), 8.82 (d, J=4.9, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.44 (s, 1H), 7.26 (d, J=4.9, 1H), 7.16 (s, 1H), 4.18 (t, J=5.5, 2H), 3.74 (s, 2H), 2.30 (s, 3H). rhSTK activity=+++
Reaction SMILES: C(OC1C=C(C=C(OCC)C=1F)C[N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:10][CH2:9]1)C.[CH:34]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([O:46][CH:47]([CH3:49])[CH3:48])[CH:45]=1)[CH:41]=[O:42])([CH3:36])[CH3:35].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH:47]([O:46][C:44]1[CH:43]=[C:40]([CH:39]=[C:38]([O:37][CH:34]([CH3:36])[CH3:35])[CH:45]=1)[C:41]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:10][CH2:9]1)=[O:42])([CH3:49])[CH3:48]
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(CO)cc(C(=O)NC2CCN(C(=O)c3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxymethyl-5-methoxy-N-piperidin-4-yl-benzamide (example 217) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 471.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=2)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:23]#[C:24][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:10]=3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cnc2cc(C3CCOCC3)nn2c1
Reactant: C#Cc1ccccc1
Product: C(#Cc1cnc2cc(C3CCOCC3)nn2c1)c1ccccc1

Procedure:
The title compound, grey solid, MS: m/e=304.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-(tetrahydro-pyran-4-yl)-pyrazolo[1,5-a]pyrimidine (example 26, step 2) and phenylacetylene.
Reaction SMILES: CCN(CC)CC.[C:8]1([S:14]([C:17]2[C:18]([S:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO.[Pd]>[C:8]1([S:14]([C:17]2[C:18]([S:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[CH:24][CH:23]=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CSc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1nn2c(N3CCN(C)CC3)ccnc2c1S(=O)(=O)c1ccccc1
Yield: 49.6 %

Procedure:
0.15 g of Pd/C (10%) and 0.3 ml of NEt3 were added to a solution of 0.189 g (0.4 mmol) of 3-benzenesulphonyl-5-chloro-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 30 ml of EtOH and hydrogenated at RT for 12 hrs. The reaction mixture was filtered over Dicalite and the filtrate was evaporated. Chromatography of the residue (SiO2, CH2Cl2/MeOH 20:1) yielded 0.08 g (49%) of 3-benzenesulphonyl-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 107-109°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH:13]=[O:14].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH2:13][OH:14]
Reactant: Cn1nnc(-c2ccccc2F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnc(-c2ccccc2F)c1CO
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
To a stirred solution of 4-(2-Fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde 4 (38 g, 185.19 mmol) under nitrogen atmosphere in methanol (300 ml) was added sodium borohydride (8.407 g, 222.23 mmol) in portion wise at 0° C. and the reaction mass stirred for 20 min. The reaction was monitored by TLC and UPLC. The reaction mixture was quenched with water (500 ml) and concentrated to remove methanol and water. Then it was extracted with ethyl acetate (4×500 ml), combined organic layer was washed with brine (50 ml), dried over sodium sulphate, filtered and concentrated to afford crude mass (34 g, 88.6% mass balance). The above solid was triturated with hexane (3×100 ml), the supernant layer was decanted and the solid was dried to afford desired product (4-(2-Fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-yl) methanol (31 g, 80.77%) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:4]([NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:3]=1.CN1CCOCC1.ClC(OC(C)=C)=O.[CH2:44]([NH2:47])[CH:45]=[CH2:46]>C1COCC1>[CH2:44]([NH:47][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:8]=1)[CH:45]=[CH2:46]
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)O)c3)ccnc2n1
Reactant: C=CCN
Agent: C=C(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CCNC(=O)c1cccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 208d (60 mg, 0.147 mmol) was dissolved in THF to which was added N-methyl morpholine (49 mg, 0.162 mmol), and isopropenyl chloroformate (36 mg, 0.295 mmol). This was stirred at room temperature for 1 hr at which time the allylamine (42 mg, 0.739 mmol) was added and the reaction mixture stirred at room temperature for another 1 hr. THF was then removed under a stream of N2 and then crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid. (8.0 mg, 9.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.92 (s, 3H), 2.74 (s, 2H), 3.86 (d, J=5.15 Hz, 2H), 5.04-5.16 (m, 2H), 5.73-5.98 (m, 1H), 6.73 (d, J=6.99 Hz, 1H), 7.10 (dd, J=7.72, 2.21 Hz, 1H), 7.27-7.43 (m, 3H), 7.51-7.65 (m, 2H), 7.69-7.82 (m, 2H), 8.54 (d, J=7.35 Hz, 1H), 8.82 (d, J=8.46 Hz, 1H); MS (ESI+) m/z 445 (M+TFA+H)+; (ESI−) m/z 443 (M+TFA−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23]C)[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][N:2]([CH3:34])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
N-[(4-Dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (3.2 g) was dissolved in methylene chloride (60 mL), and boron tribromide (0.72 mL) was added under ice-cooling. The mixture was stirred at room temperature for one day. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g). melting point: 214-217° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[CH:4][N:3]=1.[F-:16].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[CH:4][N:3]=1
Reactant: CCCOc1cnc(Cl)c2ccccc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCOc1cnc(F)c2ccccc12
Temperature: 140 °C
Yield: 68.8 %

Procedure:
To a solution of 1-chloro-4-propoxyisoquinoline (1.1 g, 4.96 mmol) in DMSO (6 mL), added CsF (1.508 g, 9.92 mmol) and heated to 140° C. for 6 h. The reaction was diluted with ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-25% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 700 mg of the desired product 1-fluoro-4-propoxyisoquinoline as a white solid. MS: MS m/z 206.17 (M++1).