Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29]C)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH:15]=[N:16][NH:17]3)[C:7]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:6][C:5]2([CH3:28])[CH3:27].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][NH:17]4)[C:7]([C:23]([F:25])([F:26])[F:24])([OH:22])[CH2:6][C:5]([CH3:27])([CH3:28])[C:4]=2[C:3]=1[OH:29]
Reactant: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2ccc(Cl)c(O)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.5 %

Procedure:
69.9 mg (0.159 mmol) of 6-chloro-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed with 1.45 ml of a one-molar solution of BBr3 in dichloromethane, and it is stirred for five hours at room temperature. After the conventional working-up, the residue is chromatographed on a Flashmaster. 28.1 mg (41.5%) of the desired compound is isolated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][CH2:12][CH2:13][S:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])(=[O:10])=[O:9].[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=1>>[CH:17]1([S:14]([CH2:13][CH2:12][CH2:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:28]2[CH:27]=[CH:26][C:25]([C:39]3[CH:44]=[N:43][C:42]([NH2:45])=[N:41][CH:40]=3)=[C:24]([F:23])[CH:29]=2)(=[O:10])=[O:9])(=[O:16])=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(CCCS(=O)(=O)C1CCCCC1)c1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CCCS(=O)(=O)C3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 1-bromo-2-((3-(cyclohexylsulfonyl)propyl)sulfonyl)benzene and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C25H28FN3O4S2, 517.15; m/z found, 518.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.59-8.51 (d, J=1.4, 2H), 8.20-8.14 (dd, J=8.0, 1.3, 1H), 7.82-7.76 (m, 1H), 7.72-7.67 (m, 1H), 7.59-7.52 (m, 1H), 7.51-7.46 (dd, J=7.7, 1.3, 1H), 7.38-7.31 (m, 2H), 3.16-3.08 (t, J=7.5, 2H), 3.08-3.01 (t, J=7.3, 2H), 2.94-2.82 (m, 1H), 2.07-1.97 (m, 4H), 1.91-1.80 (m, 2H), 1.79-1.62 (d, J=13.0, 1H), 1.48-1.35 (m, 2H), 1.35-1.25 (m, 2H), 1.24-1.12 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
A mixture of 3-(4-bromophenyl)-propylamine (6.21 g, 29 mmol), 2-bromomethyl-benzoic acid methyl ester (6.57 g, 29 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 1.5 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(4-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (7.24 g, 88%). GC/MS gave: m/z (rel.int.) 331 (M+, 9), 329 (M+, 9), 147 (100), 146 (54) 119 (34), and 91 (33). 1H NMR (300 MHz, CDCl3): δ 1.97 (dt, 2H), 2.64 (t, 2H), 3.66 (t, 2H), 4.35 (s, 2H), 7.08 (dd, 2H), 7.38 (dd, 2H), 7.46 (m, 2H), 7.51 (dt, 1H), 7.85 (d, 1H). 13C NMR (300 MHz, CDCl3): δ 29.9, 32.5, 41.9, 49.9, 119.7, 122.7, 123.6, 128.0, 130.2 (2C), 131.2, 131.4 (2C) 132.9, 140.3, 141.1, 168.5.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:20]=O)[CH:16]=[N:15]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:16]=[N:15]1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: Cc1c(C=O)cnn1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C=C2N=C(c3cccs3)OC2=O)cnn1C
Temperature: 90 °C
Yield: 42.7 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,5-dimethyl-1H-pyrazol-4-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 35 mg of the above-captioned compound.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1

Procedure:
Followed the general procedure described in Example 1c, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride coupled with methyl-piperazine to give the desired product 3a, 600 mg (53%). LC-MS (m/z) 372.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]([OH:31])[CH3:30])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]([OH:31])[CH3:30])=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1c(C(C)O)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1c(C(C)O)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)O
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of Example 272A (79 mg, 0.22 mmol) in methanol (8 mL) and water (1.0 mL) was treated with 10% Pd/C (160 mg) and stirred under hydrogen for 16 hours. Filtration and solvent evaporation gave the desired compound (51 mg). 1H NMR (DMSO-d6) δ 1.23 (s, 3H), 2.21 (s, 3H), 4.87 (m, 1H), 5.06 (br s, 1H), 6.82 (d, 1H), 7.36-7.41 (m, 3H), 7.78-7.82 (m, 2H), 10.4 (s, 1H), 13.2 (br s, 1H); MS (ESI(−)) m/e 352 (M−H)−.
Reaction SMILES: P(O[C:18]([CH3:49])=[C:19]([N:33]1[C:39](=[O:40])[CH:38]2[CH:34]1[S:35][C:36]([CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[N:37]2)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.O>C(OCC)(=O)C>[O:42]([CH2:41][C:36]1[S:35][CH:34]2[CH:38]([C:39](=[O:40])[N:33]2[C:19](=[C:18]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH3:49])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[N:37]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(OP(=O)(Oc1ccccc1)Oc1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of diphenyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate (7.02 g) in ethyl acetate (70 ml) at 0°-5° C. was added morpholine (1.83 ml) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (30 ml) was added and the organic layer was separated, washed with water (30 ml) and saturated sodium chloride solution (30 ml), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow foam in almost quantitative yield. TLC (silica) Rf 0.57 (ethyl acetate). The product was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond. NMRδCDCl3 1.93 (s), +2.43 (s) (3H), 3.17-3.93 (m, 8H), 4.90 (s, 2H), 5.25 (s, 2H), 5.68-6.13 (m, 2H) and 6.87-7.7+8.1-8.4 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(O)c(Br)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.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>[CH:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)OC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)OC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 97.6 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (18.0 mg, 0.094 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0 mg, 0.094 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (250.0 mg, 98%) was isolated by chromatography (0-3% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(#N)C>[CH2:37]([N:15]1[N:16]=[N:17][C:13]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:14]1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCCCCCCCCCCCBr
Reactant: CCOC(=O)C(c1ccccc1)c1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCn1nnc(C(C(=O)OCC)c2ccccc2)n1
Temperature: 25 °C

Procedure:
The tetrazole ester (a) (47 g; 0.20 moles) was dissolved in acetonitrile (550 mL) containing one equivalent of triethylamine (20.2 g; 0.20 moles). The solution was heated to reflux and then 1-bromododecane (49.8 g; 0.20 moles) was added dropwise over 20 minutes. Upon completion, the solution was heated to reflux for 16 hours, cooled to room temperature, and concentrated in vacuo. The residue was triturated with ethyl acetate (1 L), filtered, and the filtrate was washed with aqueous HCl (1N), brine, and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent concentrated in vacuo, leaving a viscous liquid containing both 1- and 2-isomers. The regioisomers were separated by silica gel chromatography using 75% hexane and 25% ethyl acetate as the eluent, obtaining the title compound as a colorless liquid. Yield: 33 g (41%).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:6]=1)C.[ClH:18]>>[ClH:18].[CH2:15]([N:12]([CH2:13][CH3:14])[C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[N:8]=1)[C:4]([OH:17])=[O:3])[CH3:16]
Reactant: CCOC(=O)c1cc(C)nc(N(CC)CC)c1
Agent: Cl
Product: CCN(CC)c1cc(C(=O)O)cc(C)n1

Procedure:
A solution of 2-diethylamino-6-methyl-isonicotinic acid ethyl ester (6.39 g, 27.0 mmol) in 6 N aq. HCl (100 mL) is stirred at 80° C. for 72 h before the solvent is removed in vacuo. The remaining solid is dried under HV to give 2-diethylamino-6-methyl-isonicotinic acid hydrochloride (6.96 g) as a yellow solid; LC-MS: tR=0.53 min; [M+H]+=209.09; 1H NMR (D6-DMSO): δ 1.17 (t, J=6.8 Hz, 6H), 2.51 (s, 3H), 3.68 (q, J=6.3 Hz, 4H), 6.96 (s, 1H), 7.15 (s br, 1H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:10][N:11](C)[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrCCCCC1(C2C=CC(NC(=O)C(F)(F)F)=CC=2)[S:52][CH2:51][CH2:50][S:49]1>>[Si:1]([O:8][C@H:9]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])=[CH:19][CH:18]=2)[S:52][CH2:51][CH2:50][S:49]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(Nc1ccc(C2(CCCCBr)SCCS2)cc1)C(F)(F)F
Reactant: CN(CCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCC1(c2ccc(NC(=O)C(F)(F)F)cc2)SCCS1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 102, using Intermediate 45 in place of Intermediate 98. ES/MS calcd. for C32H43F3N3O4S2Si+ 682.2. Found m/z=682.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:22]([C:18]2[S:17][C:16](/[CH:15]=[CH:14]/[C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:20][C:19]=2[CH3:21])=[O:23])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)NC1CCOCC1
Yield: 68 %

Procedure:
As described for example 6f, 2-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.22 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (63 mg, 68%) which was obtained as a light yellow solid. MS: m/e=428.3 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([OH:16])[CH:14]=[CH:13][CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1.CSC>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([OH:16])[C@H:14]2[C@H:13]([O:25]2)[CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OCC=C[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1OC[C@H]2O[C@H]2[C@@H]1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C., stirred solution of cis-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol (0.200 g, 0.91 mmol) in CH2Cl2 (15 ml) was added m-CPBA (75%, 0.46 g, 2.68 mmol) and the mixture was stirred for 1 H at 0° C. Dimethyl sulfide (0.01 ml) was added and stirring was continued for 10 min. The solvent was removed in vacuo and the crude product was diluted with EtOAc (30 ml). The resulting solution was washed successively with saturated aqueous Na2CO3 (10 ml), water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (25-40% EtOAc in hexane).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2ccc(Cl)cn2)c1

Procedure:
3-Hydroxy-benzonitrile was reacted with 2,5-dichloro-pyridine according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 231 (M)+, 233 (M+2)+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:43])[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:41][N:40]([CH3:42])[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[F:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:43])=[O:39]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(CC(=O)N(C)C)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(=O)N(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide (Step 119.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 551.1 [M+H]+; tR=3.81 min (System 1); TLC: Rf=0.36 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([NH:9][C@H:10]([C:12]2[N:17]=[C:16]3[CH:18]=[CH:19][N:20]([CH3:21])[C:15]3=[CH:14][C:13]=2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH3:11])[C:6]([Cl:28])=[CH:5][N:4]=1.[OH-].[NH4+]>CO>[Cl:28][C:6]1[C:7]([NH:9][C@H:10]([C:12]2[N:17]=[C:16]3[CH:18]=[CH:19][N:20]([CH3:21])[C:15]3=[CH:14][C:13]=2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH3:11])=[N:8][C:3]([NH2:1])=[N:4][CH:5]=1
Reactant: C[C@H](Nc1nc(Cl)ncc1Cl)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Nc1nc(N)ncc1Cl)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A 7 N solution of ammonia (1 mL, 7.00 mmol) in MeOH was added to (S)-2,5-dichloro-N-(1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidin-4-amine (20 mg, 0.050 mmol) while stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then at 100° C. in a microwave reactor for 1 hour. The mixture was concentrated, dissolved in dioxane (1 mL), and treated with ammonium hydroxide (1 mL, 7.19 mmol). The mixture was heated at 100° C. in a microwave reactor for 12 hours. The reaction was concentrated and purified by preparative HPLC (basic mode, 25% to 50% ACN/water gradient) to give the title compound as an off-white solid (13.7 mg, 72.0%). 1H NMR (500 MHz, CD3OD) δ ppm 1.42 (d, J=6.35 Hz, 3 H), 3.66 (s, 3 H), 3.90 (s, 3 H), 5.46 (q, J=6.51 Hz, 1 H), 6.45-6.49 (m, 1 H), 6.69-6.72 (m, 1 H), 7.65 (d, J=2.93 Hz, 2 H), 7.69 (s, 1 H), 7.84 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19ClN8, 383.14; found 383.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[OH:27]S(O)(=O)=O>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10](=[O:27])[CH3:11])[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Yield: 72.5 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynylbenzoic acid methyl ester (7.11 g, 18.1 mmol), HgSO4 (5.43 g, 18.1 mmol), and conc. H2SO4 (1.92 mL, 36.1 mmol) in acetone-water (150 mL/25 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with EtOAc-THF, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was triturated with MeOH to afford the desired product (4.46 g, 73%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.Cl.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:30][C:27]([F:28])([F:29])[C:4]1[CH:3]=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([CH2:33][NH2:32])=[CH:35][CH:36]=2)[C:10]2[NH:9][C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:5]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Agent: Cl
Product: NCc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc1

Procedure:
The title compound was prepared from 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (Example 7) and 4-aminomethylphenylboronic acid hydrochloride (Acros) under the conditions of Example 51a and isolated as a white amorphous solid. MS (ESI, pos. ion) m/z: 521 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5](=[O:8])([OH:7])[OH:6].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:27]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]I)=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CCN(C(C)C)C(C)C.Cl>CO>[CH2:27]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:1][CH2:2][CH2:3][CH2:4][P:5](=[O:7])([OH:6])[OH:8])=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCc1ccc(CI)cc1
Reactant: NCCCP(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCCCCCCc1ccc(CNCCCP(=O)(O)O)cc1
Reaction time: 12 h
Yield: 19.3 %

Procedure:
3-Aminopropylphosphonic acid (0.060 g, 0.436 mmol) and tetrabutylammonium hydroxide (1.0M in methanol, 0.44 mL, 0.43 mmol) in methanol (3 mL) were heated at 50° C. for 15 min until all of the solids had dissolved. 4-(Nonyl)benzyliodide (0.100 g, 0.291 mmol) and DIEA (0.112 g, 0.872 mmol) were added and stirring was continued for 12 h at 50° C. The reaction was made acidic (pH˜5) by the addition of concentrated hydrochloric acid then directly purified using LC-3 to give the title compound (0.020 g): 1H NMR (500 MHz, CD3OD) δ 7.39 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.15 (s, 2H), 3.14 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H), 2.00 (m, 2H), 1.79 (td, J=5.3, 18.5 Hz, 2H), 1.61 (m, 2H), 1.24-1.36 (m, 14H), 0.89 (t, J=7.0 Hz, 3H); ESI-MS 356.2 (M+H).