Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH3:25])[CH2:19][CH2:18]4)=[N:14][C:13]([CH2:26][CH2:27]O)=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:29]([N:31](CC)[CH2:32][CH3:33])[CH3:30].CS(Cl)(=O)=O.N1CCCC1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH3:25])[CH2:19][CH2:18]4)=[N:14][C:13]([CH2:26][CH2:27][N:31]4[CH2:32][CH2:33][CH2:30][CH2:29]4)=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COCC1CCN(c2nc(CCO)nc3scc(-c4ccc(F)cc4)c23)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: COCC1CCN(c2nc(CCN3CCCC3)nc3scc(-c4ccc(F)cc4)c23)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
2-[5-(4-Fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (20 mg, 0.05 mmol) was dissolved in THF (1 mL) to which was added triethylamine (0.021 mL, 0.15 mmol) and methanesulfonyl chloride (0.1 mmol). The reaction was stirred at 50° C. for 2 hrs then pyrrolidine (18 mg, 0.25 mmol) was added and the reaction stirred at 50° C. overnight. The reaction was partitioned between water and DCM. The organics wre concentrated in vacuo and the residue purified by preparative TLC, eluting with 7.5% 7M ammonia in methanol/DCM v/v to give 5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]-2-(2-pyrrolidin-1-ylethyl)thieno[2,3-d]pyrimidine (10 mg). LCMS RT=3.28 min. M+1=455.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.Cl.Cl.[O:47]=[C:48]1[NH:56][C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[N:49]1[CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1.CS(C)=O>[O:24]=[C:3]1[C@H:2]([NH:1][C:35]([N:60]2[CH2:61][CH2:62][CH:57]([N:49]3[C:50]4[C:51](=[N:52][CH:53]=[CH:54][CH:55]=4)[NH:56][C:48]3=[O:47])[CH2:58][CH2:59]2)=[O:36])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) (0.150 g, 0.45 mmol) and 4-nitrophenylchloroformate (0.091 g, 0.45 mmol) in dry tetrahydrofuran (2.5 mL) was cooled to 0° C. under argon. Triethylamine (0.063 mL, 0.45 mmol) was added and the reaction stirred for 1 h. A solution of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (0.130 g, 0.45 mmol) and triethylamine (0.190 mL) in dimethylsulfoxide (2.5 mL) was added. The reaction was allowed to come to room temperature and stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution). The pure fractions were extracted with methylene chloride and saturated sodium bicarbonate. The organic layer was dried, filtered and evaporated. The product was taken up in methanol and treated with hydrogen chloride. The solvent was evaporated and the resulting solid was dried in vacuo, to yield the title compound (184 mg, 66% yield). MS 578.2118 (M+1) 1H NMR (500 MHz, C3OD) δ 8.02 (d, J=8 Hz, 1H), 8.00 (d, J=6 Hz, 1H), 7.80 (d, J=3 Hz, 2H), 7.60 (m, 3H), 7.50 (t, J=8 Hz, 2H), 7.45 (m, 1H), 7.39 (d, J=7 Hz, 1H), 7.34 (dd, J=6, 8 Hz, 1H), 5.55 (s, 1H), 5.26 (m, 1H), 4.61 (m, 2H), 4.35 (d, J=13 Hz, 2H), 3.08 (q, J=13 Hz, 2H), 2.40 (m, 2H), 1.91 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCO)cc1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A suspension of 2-(4-nitrophenoxy)ethanol (Aldrich) (2 g, 10.9 mmol) and Pd/C (Aldrich, 10%, 0.2 g) in methanol (50 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-(4-amino-phenoxy)-ethanol as a light yellow solid (1.6 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21]COC)=[C:6]([CH:20]=1)[C:7]([C:9]1[C:14]([CH:15]2OCC[O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCOc1ccc(Cl)cc1C(=O)c1ncccc1C1OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1cccnc1C(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 27 h
Yield: 79.6 %

Procedure:
A mixture of 2-(5-chloro-2-methoxymethoxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine (3.41 g), hydrochloric acid (5.0 ml) and THF (35 ml) was stirred for 27 hours at room temperature. The reaction mixture was neutralized with an aqueous solution of sodium hydroxide, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, then the solvent was distilled off to leave 2-(5-chloro-2-hydroxybenzoyl)-3-formylpyridine (2.03 g) (Compound E-10). The physical properties and spectrum data are shown in Table 16 and Table 18.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[N:25]([CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:38]([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:21]=[N:20][N:19]([CH3:38])[CH:18]=2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:27])(=[O:28])[N:25]([CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cn[nH]c3)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1cc(C=Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-{2-benzyloxy-4-[2-(1H-pyrazol-4-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (example 40, step C) (114 mg, 0.224 mmol), MeI (0.05 mL, 0.80 mmol) and K2CO3 (60 mg, 0.43 mmol) in CH3CN (3 mL) is stirred at RT for 2 days. The mixture is partitioned between EtOAc and aq. NaHCO3. The organic phase is dried over MgSO4 and concentrated to afford the crude product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[CH:22][CH:23]=3)[N:18]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH:17]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([N:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[CH:22][CH:23]=3)[N:18]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH:17]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCNCC4)ccc23)cc1
Reaction time: 3 h
Yield: 61.7 %

Procedure:
Trifluoroacetic acid (46 μL, 0.059 mmol) was added to a mixture solution of tert-butyl 4-(3-(4-methoxyphenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (29 mg, 0.059 mmol) in methylene chloride (1 mL) at room temperature. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure. After adding ethyl acetate and saturated sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound (14 mg, 64%) was obtained as yellow solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 17.8 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A2, 0.55 g, 2.04 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.79 g, 2.55 mmol), Pd(PPh3)4 (118 mg, 0.102 mmol) and Cs2CO3 (1.0 g, 3.27 mmol) to afford the title compound (0.135 g, 18%) as a yellowish oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCBr
Product: N#Cc1ccc(-c2ccc(OCCCCBr)cc2)cc1
Yield: 31 %

Procedure:
A solution of 4'-hydroxy-4-cyanobiphenyl (11.7 g, 60 mmol) was treated with 1,4-dibromobutane (38.9 g, 0.18 mol, 216) as described in Example 1. Recrystallization of the product from ethanol gave 4'-(4-bromobutyloxy)-4-cyanobiphenyl (6.15 g, 31%): mp 62.5-64° C.; 1H NMR (CDCl3) 7.52(s, 4H), 7.41 and 6.83(2d, 4H), 3.95(t, 2H), 3.42(t, 2H), 1.97(m, 4H); IR (KBr) 2225, 1605, 1581 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.N[C@@H:12]1CC[C@H](C(OC)=O)C[CH2:13]1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Product: CCOC(=O)[C@H]1CC[C@@H](N)CC1

Procedure:
The title compound was prepared from cis-4-aminocyclohexanecarboxylic acid using a method analogous to cis-methyl 4-aminocyclohexanecarboxylate.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH2:24][CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Product: CC[C@@H]1COC(=O)N1c1cnc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1
Yield: 85.2 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (113 mg) described in Preparation Example 232 and (R)-4-ethyloxazolidin-2-one (52 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (105 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[N:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ncc(NC2CCNCC2)cn1

Procedure:
A solution of 4-(pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 4.67 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 179.1 [M+H]+.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13](S(C)(=O)=O)=[C:14]([C:26]#[N:27])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13]([CH2:4][CH3:5])=[C:14]([C:26]#[N:27])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Reactant: CC[Zn]CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Add diethylzinc (1.0M in hexanes, 16 mL, 16 mmol) to a solution of 3-(4-tert-butyl-phenyl)-4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (2.78 mmol) in 15 mL of anhydrous CH2Cl2 and stir under nitrogen at room temperature for 5 days. Cool to 0° C. and carefully quench with ice followed by 10 mL of saturated NH4Cl. Filter the mixture through Celite® and rinse the filter pad with 100 mL of CH2Cl2. Wash the combined organic layers with brine (1×20 mL), dry over Na2SO4, filter and evaporate. Chromatograph over silica gel with 100% toluene to give the title compound as a clear oil, 625 mg (66%). MS (FAB)=341 (M+); HPLC=98%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=1)[CH3:2].[NH2:31][C:32]1[CH:33]=[C:34]([C:43]([F:46])([F:45])[F:44])[C:35]([C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[N:36][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:31][C:32]2[CH:37]=[N:36][C:35]([C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[C:34]([C:43]([F:46])([F:44])[F:45])[CH:33]=2)=[O:29])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: CC(C)(CO)c1ncc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Yield: 26.2 %

Procedure:
A solution of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (50 mg, 0.122 mmol), 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol (28.5 mg, 0.122 mmol), HATU (92 mg, 0.243 mmol) and DIEA (0.064 mL, 0.365 mmol) in DCM (10 mL) was stirred at 25° C. After LCMS analysis showed the starting material was consumed, the mixture was washed with H2O. The organic layer was washed with brine and dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC (DCM/MeOH=20/1) to yield 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (20 mg, 0.032 mmol, 26% yield): 1H NMR (400 MHz, CD3OD) δ 8.95 (br. s., 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.43-7.39 (m, 3H), 7.30-7.24 (m, 2H), 6.95-6.91 (m, 2H), 6.48 (s, 1H), 5.30 (s, 2H), 4.16-4.11 (m, 2H), 3.87-3.79 (m, 6H), 1.40-1.38 (m, 9H); ES-LCMS m/z: 628.3 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Br:30])=[CH:9][C:10]=1[CH2:11][N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)C.CC(C)([O-])C.[K+]>C1COCC1>[CH2:17]([O:16][C:14]([CH:13]1[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[CH2:11][C:10]2[CH:9]=[C:8]([Br:30])[S:7][C:6]=2[C:4]1=[O:3])=[O:15])[CH3:18]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Br)sc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2sc(Br)cc2CN1Cc1ccc(OC)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-3-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiophene-2-carboxylic acid ethyl ester (example 21.b, 7.0 g, 14.1 mmol) was dissolved in 140 mL of anhydrous THF and cooled to −15° C. in a brine dry ice bath. A solution of 30 mL of 1.0 M potassium tert-butoxide in UV was added slowly to cold solution, and the reaction mixture was stirred at −15° C. for 30 min. and then at room temperature for 2 hours. The reaction was quenched with 29 mL of 1N HCl, and 400 mL ammonium chloride, and extracted twice with 300 mL ethyl acetate. The organic fractions were washed with brine, dried over anhydrous sodium sulfate and concentrated to 5.67 g of a tan viscous oil: MS: (+) m/z 453.6, 455.5 (M+1, 79Br/81Br)
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19]([NH2:25])=[N:20][C:21]([SH:24])=[N:22][CH:23]=2)=[O:17])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CC#N.O>CC(C)=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][S:24][C:21]1[N:20]=[C:19]([NH2:25])[C:18]([C:16](=[O:17])[NH:15][C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)=[CH:23][N:22]=1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(S)ncc1C(=O)Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of ethyl bromoacetate (0.128 g, 0.76 mmol) in acetone (2 mL) was added to a suspension of 4-amino-2-mercaptopyrimidine-5-carboxylic acid (4-fluorophenyl)amide (0.10 g, 0.38 mmol) and Na2CO3 (80 mg, 0.76 mmol) in acetone (5 mL). After stirring at ambient temperature for 2 hours, the resulting suspension was filtered and the filtrate concentrated to afford a crude solid that was recrystallized in dichloromethane/hexanes, or alternatively CH3CN/H2O) to afford the titled compound as a white solid (100 mg, 0.29 mmol, 76% yield). 1H NMR (300 MHz, d6-acetone) δ 9.60 (bs, 1H), 8.67 (s, 1H), 7.75 (m, 1H), 7.56 (m, 2H), 4.15 (m, 2H), 3.92 (s, 1H), 1.22 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(C#N)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-cyano-phenylboronic acid to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-yl]-benzonitrile LC-MS m/e 356(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14](=O)[CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[CH:13]=[C:14]([CH3:15])[N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:9]=32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(cc(C)n1C[C@@H](C)O)C2
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A solution of 1.45 g of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone and 60 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 90 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.05 g (61%) of (R)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow solid with m.p. 110°.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][NH:10][N:9]=1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O1CCOCC1>[NH2:7][C:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=1
Reactant: Clc1ncccn1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ncccn2)nc1N
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (2.4 g, 21.23 mmol) is added to a mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (3.0 g, 19.3 mmol) and 2-chloropyrimidine (2.2 g, 19.3 mmol) in 50 mL of anhydrous dioxane. The reaction mixture is heated to 100° C. and stirred for 2 h. The solvent is removed in vacuo, and the residue is partitioned between EtOAc and water (50 mL each). The aqueous layer is extracted two more times with EtOAc (40 mL each), and the combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a yellow/brown oily solid. This crude product is triturated with EtOAc to give the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:12]=2)[N:6]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)[C:4]=1[C:34]#[N:35].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>CN(C=O)C.CO>[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3[CH2:19][CH2:20][N:21]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:22][CH2:23]3)[N:12]=2)[N:6]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)[C:4]=1[C:34]#[N:35]
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN4CCNCC4)n3)nc(N)c2C#N)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN4CCN(Cc5ccccc5)CC4)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
The compound of Example 18 (146 mg), benzaldehyde (28 mg) and triethylamine (75 mg) were dissolved in a mixture of 1 mL of DMF and 2 mL of methanol, the resulting mixture was stirred at room temperature overnight. To the reaction mixture under ice temperature, 30 mg of sodium cyanoborohydride was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, thereto ice-water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=600:20:1) to give 60 mg of N-(4-{6-amino-2-[6-(4-benzylpiperazin-1-ylmethyl)pyridin-2-ylmethylsulfanyl]-5-cyanopyrimidin-4-yl}phenyl)acetamide as a white powder.