Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].F[B-](F)(F)F.[H+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][C:25]([N+]#N)=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>CS(C)=O.O>[C:1](=[O:4])([S:3][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[N:23][C:22]=2[CH:24]=1)[CH3:2]
Reactant: N#[N+]c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: CC([O-])=S
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Sc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 3.4 %

Procedure:
To a stirred solution of potassium thioacetate (130 mg, 1.13 mmol) in DMSO (2.8 mL) at room temperature was added dropwise a solution of 2-(4-chlorophenyl)benzo[d]oxazole-5-diazonium tetrafluoroboric acid salt (370 mg, 1.08 mmol) in DMSO (1.4 mL). After 15 min, the mixture was heated at 70° C. for 1 h. After cooling, the mixture was diluted with water, and then extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 5:95 v/v to ethyl acetate/hexanes 15:85 v/v) and triturated with diethyl ether/hexanes to afford 11.3 mg (3%) of the title compound (LCMS RT=7.89 min, MH+ 304.2)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9](=O)([O:17]C1C=CC([N+]([O-])=O)=CC=1)[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>C1COCC1>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:9]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.5 g of 4-piperidinylmethanol were dissolved in 170 ml of THF. 25.8 g of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate and 15.9 ml of N,N-diisopropylethylamine were successively added thereto. The mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The residue was taken up in 400 ml of ethyl acetate and washed once with 300 ml of 0.5 N HCl and twice with 250 ml of 1 N NaOH each time. The organic phase was dried with MgSO4, the solvent was removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C[C:12]([N:14](C)C)=O>CCOC(C)=O>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:12]#[N:14])[C:3]=2[CH:10]=[CH:9]1
Reactant: CC(=O)N(C)C
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CCOC(C)=O
Product: N#Cc1ccnc2[nH]ccc12
Temperature: 150 °C

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (10.13 g, 66.4 mmol) was dissolved into DMAC (100 mL). This solution was filtered to remove insoluble particles. N2 was purged into the solution while adding the following reagents: 4.68 g Zn(CN)2, 1.476 g dppf, 0.519 g Zn, and 1.227 g Pd2(dba)3. The greenish brown mixture was heated to 150° C. for 4 h. After cooled to RT, the mixture was filtered through a pad of Celite® and silica to remove Zn and Pd. The pad was washed with EtOAc and CH2Cl2. The filtrate was concentrated and the residue was taken into 500 mL EtOAc. This organic solution was washed with 10% NH4OH (500 mL) and sat'd NaCl (500 mL), dried over Na2SO4, filtered and concentrated to afford a dark residue, which was taken into 100-200 mL of EtOAc and resulting precipitate of 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile was collected.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][C:15]([CH3:37])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1.I[CH3:39].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:39])[C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][C:15]([CH3:37])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(C)cc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(C)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.5 mg, 0.062 mmol) was added to a solution of 1-{3-[2-(4-chlorophenyl)-5-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Example 119, 20 mg, 0.041 mmol) in N,N-dimethylformamide (1 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (5 μl, 0.12 mmol) was added and the mixture was stirred at room temperature for 10 min. Water (25 mL) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4), the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (35:65) to give the title compound as a pale yellow foam (20 mg, 97%). 1H NMR (360 MHz, CDCl3) δ7.48-7.43 (3H, m), 7.33-7.31 (2H, m), 7.24-7.21 (1H, m), 7.11-7.02 (2H, m), 6.91-6.84 (3H, m), 3.86 (3H, s), 3.76 (2H, m), 3.53 (3H, s), 3.38 (2H, m), 3.04 (2H, m), 2.94 (2H, m), 2.77 (2H, m), 2.57 (2H, m), and 2.49 (3H, s). m/z (ES+) 502, 504 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:17]C)(OC)[CH3:14])=[CH:9][CH:8]=1.[CH3:19][C:20]1([CH3:29])[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22](=[O:28])[CH2:21]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:28][C:22]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:17])[CH3:14])=[CH:11][CH:12]=2)[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21]1
Reactant: COC(C)(OC)c1ccc(Br)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2(O)CC(C)(C)CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
27.5 ml of a 1.6 M solution of n-butyllithium in hexane are added dropwise at −78° C. to a solution of 10 g of 1-bromo-4-(1,1-dimethoxyethyl)benzene (compound Vp) in 100 ml of tetrahydrofuran. The reaction mixture is stirred for 2 hours at this temperature. A solution of 6.92 ml of 3,3,5,5-tetramethylcyclohexanone in 20 ml of tetrahydrofuran is added over 20 minutes and the reaction mixture is stirred at −78° C. for 1 hour. After warming to room temperature, 140 ml of saturated aqueous ammonium chloride solution are added. The phases are separated after settling has taken place, the aqueous phase is extracted with diethyl ether, the organic phases are combined and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel, eluting with a 95/5 (v/v) cyclohexane/ethyl acetate mixture; yield=88%; m.p.=135° C. The following compounds are prepared in the same way:
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH3:51][O:52][C:53](=[O:62])[CH2:54][CH2:55][C:56]1[CH2:60][CH2:59][C:58](=[O:61])[CH:57]=1.CCCCCC>C(OCC)(=O)C>[CH3:51][O:52][C:53](=[O:62])[CH2:54][CH2:55][CH:56]1[CH2:60][CH2:59][C:58](=[O:61])[CH2:57]1
Reactant: COC(=O)CCC1=CC(=O)CC1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CCC1CCC(=O)C1
Yield: 88.1 %

Procedure:
General procedure B using (S)-p-tol-BINAP and 3-(3-oxo-cyclopent-1-enyl)-propionic acid methyl ester (0.084 g, 0.5 mmol) gave, after 24 h at 0° C. and flash chromatography (4:1, then 2:1 hexane:ethyl acetate), the title compound as a clear oil (0.075 g, 88% yield). Spectroscopic data were consistent with previously reported data for this compound.15 [α]D25° C.−112° (c 1.3, CHCl3). Conversion of the title compound to the corresponding benzyl ester followed by chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 91% ee.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:15][CH:16]=2)=[N:9][N:8]=[N:7]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:10]5[N:9]=[N:8][N:7]([CH2:2][CH:3]([CH3:5])[CH3:4])[N:6]=5)[CH:12]=4)=[CH:36][C:21]=3[C:22]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:26][CH:27]=1
Reactant: CC(C)CBr
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(CC(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 37.6 %

Procedure:
1-bromo-2-methylpropane (23 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (15 mg, 38%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.56 (1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.63 Hz), 7.99-8.04 (2H, m), 7.87-7.94 (2H, m), 7.79-7.84 (1H, m), 7.73-7.78 (1H, m), 7.70 (1H, t, J=7.63 Hz), 7.41 (2H, t, J=8.70 Hz), 4.62 (2H, d, J=7.32 Hz), 2.87 (3H, d, J=4.27 Hz), 2.31-2.39 (1H, m), 0.95 (6H, d, J=6.71 Hz). LC-MS retention time: 2.09 min; m/z (MH+): 470. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=16.08 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.89 min, purity=99%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[S:31]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[CH:4][CH:3]=1)(=[O:32])=[O:30]
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CCOCC3)c12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CCOCC3)c12
Reaction time: 0.17 h

Procedure:
To a solution of (4-hydroxy-8-methylnaphthalen-1-yl)(morpholino)methanone (above Step-7 intermediate) (1 equiv) in dry CH2Cl2 (4 mL) under nitrogen was added DIPEA (3 equiv) at 0° C. and the mixture was stirred for 10 min. To this, Tf2O (1.5 equiv) was added drop wise and the reaction mixture was stirred for another 1.5 h at 0° C. Then it was slowly quenched with water (10 mL) and the aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and the residue was purified by column to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:30](I)[CH2:31][CH2:32][CH3:33]>O>[CH2:30]([N:1]([CH2:4][CH2:5][CH2:10][CH3:9])[C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCI
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 122.4 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.34 mmol) and N,N-dimethylformamide (2 ml) was added sodium hydride (60% in oil, 27 mg, 0.66 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-BuI (184 mg, 1.00 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give 85 mg (62%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39]>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH:12]=[C:13]([NH:39][C:38]2[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:36]([F:35])[CH:37]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(F)cc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 2-(4′-chloro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3-fluoro-5-(trifluoromethyl)aniline under the conditions described in Example 37, step (b). Mass spectrum (ES-, m/z): 560, 562 (M−H);
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])OCC)[CH2:9][CH2:8]2)[CH:6]=1.N[C:16]1[C:21]([NH2:22])=[CH:20][N:19]=[C:18]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:17]=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]3[NH:14][C:20]4[C:21]([N:22]=3)=[CH:16][N:17]=[C:18]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])[CH2:24]3)[N:19]=4)[CH2:8][CH2:9]2)[CH:6]=1
Reactant: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2cc(F)cn2)CC1
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ncc3nc(C4(n5cc(F)cn5)CC4)[nH]c3n2)C1)N1CCCC1

Procedure:
Ethyl 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarbimidate (148 mg, 0.75 mmol) and acetic acid (0.8 mL) were added to the filtrate containing (R)-(1-(4,5-diaminopyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared in the previous step. The reaction mixture was heated at reflux for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-4% methanol in ethyl acetate) to afford the title compound. MS (ES+APCI) (M+H) 425.2; LCMS retention time: 3.545 min (Method V1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:10][S:11]([O:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([N:8]([S:11]([CH3:10])(=[O:13])=[O:12])[CH3:9])[CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: CN[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN([C@H]1CC[C@@H](OS(C)(=O)=O)CC1)S(C)(=O)=O

Procedure:
Prepared by reacting cis-1-hydroxy-4-methylamino-cyclohexane with methanesulphonic acid chloride in tetrahydrofuran in the presence of triethylamine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]3[N:29]=[C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:27]=[CH:26][N:25]=3)[CH:17]=2)=[O:14])=[CH:11][CH:10]=1>C(O)C.O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:37][CH:36]=2)=[CH:17][C:18]=1[NH:23][C:24]1[N:29]=[C:28]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
25.8 g (300 mmol) of piperazine are suspended in a mixture of 25 ml of ethanol and 25 ml of water. After almost a clear solution has formed, 12.9 g (30 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide are added step by step. The yellow solution is boiled under reflux for 14 hours, cooled to room, temperature and filtered over Celite. 100 ml of water is added to the solution, the ethanol is evaporated under vacuum and 30 ml of 1N NaOH is added, leading to crystallization of the product. Drying at 50 mbar and 60° C. yields N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide; Rf=0.15 (methylene chloride:ethyl acetate:methanol:conc. aqueous ammonium hydroxide solution=60:10:30:2); tR (HPLC)2) 14.6 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:14]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCc1cnc(Cl)nc1
Reactant: COc1ccc(CCN)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Yield: 67.5 %

Procedure:
A mixture of 2-(3-bromo-4-methoxyphenyl)ethanamine (1 g; 4.35 mmol), 2-chloro-5-ethyl-pyrimidine (0.56 g; 3.92 mmol) and DIEA (0.84 g; 6.53 mmol) in n-butanol was heated to reflux for 14 hr. Upon cooling, the reaction mixture was concentrated and partitioned between 1N HCl and ether. The aqueous phase was basified with 6N NaOH and extracted with ether. The combined organic phases were washed with a saturated solution of NaHCO3, dried over MgSO4, filtered and concentrated to provide a colorless solid, which was triturated with hexane, filtered and dried to provide the title compound as a white crystalline solid (0.89 g; 67% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([SH:10])[C:7]([CH3:11])=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:2][C:3]1[CH:9]=[C:8]([S:10][C:18]2[CH:17]=[CH:16][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[Cl:12])[C:7]([CH3:11])=[CH:6][C:4]=1[NH2:5]
Reactant: Cc1cc(N)c(F)cc1S
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)c(F)cc1Sc1ccc(C(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 73 %

Procedure:
1.00 Gram of 2-fluoro-5-methyl-4-mercaptoaniline hydrochloride, 2.24 g of 3,4-dichlorobenzotrifluoride and 1.59 g of potassium carbonate were dissolved in 10 ml of dimethylformamide, and the resulting solution was stirred for 6 hours at a temperature of from 110° to 120° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with two 100-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 1.27 g of 2-fluoro-5-methyl-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.CO.[C:37](=O)([O-])[O-:38].[K+].[K+]>>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][O:38][CH3:37])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Agent: [K+]
Solvent: CO
Product: COCc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 110 °C
Yield: 17 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (25 mg, 0.051 mmol) was placed in methanol (1.5 ml, 37.1 mmol) and potassium carbonate (7.05 mg, 0.051 mmol) added. The mixture was heated under microwave irradiation at 110° C. for 20 mins. The solvent was removed and the residue purified by Mass Directed Automated Preparative HPLC to give the title compound as a white solid (3 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15][O:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1cccc(C)c1CCl
Reactant: COc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C=O)cccc1OCc1c(C)cccc1C

Procedure:
The solution of 3-hydroxy-2-methoxybenzaldehyde (5.06 g, 32.7 mmol), 2,6-Dimethylbenzyl chloride (5.04 g, 33.1 mmol) and K2CO3 (4.78 g, 34.6 mmol) in dry DMF (15 ml) was stirred at room temperature under argon for 16 hours, then diluted with EtOAc (40 ml), and washed with water (20 ml). The organic layer was concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound as an off white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.CCN(CC)CC.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl>[CH2:11]([O:10][C:8]([C:6]1[O:7][C:3]([CH2:2][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][CH:5]=1)=[O:9])[CH3:12]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CN2CCOCC2)o1
Temperature: 45 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a solution of ethyl 5-(chloromethyl)-2-furan-carboxylate (0.5 mL, 3.25 mmol) and Et3N (0.9 mL, 6.5 mmol) in dichloromethane under nitrogen was added morpholine (284 μL, 3.25 mmol) dropwise and a catalytic amount of KI. The reaction mixture was stirred at 45° C. for 24 hours, then it was concentrated in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with water (2×) then brine, dried over sodium sulfate, filtered, concentrated, and dried in vacuo to give 520 mg (67% yield) of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid ethyl ester as a light brown oil. 1H-NMR (d6-DMSO) δ: 7.22 (d, 1H), 6.51 (d, 1H), 4.25 (q, 2H), 3.54 (m, 6H), 2.37 (broad s, 4H), 1.27 (t, 3H).