Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[C:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH3:27].Cl>O.O1CCOCC1>[C:26]([NH:29][C:30]1[CH:35]=[C:34]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)c1

Procedure:
A first stock solution was prepared consisting of 2-(4-iodo-phenoxymethyl) -thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 1.56 g, 4 mmol), bis(tri -cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 140 mg, 0.21 mmol), and dioxane (approximately 82 mL). A second stock solution was prepared consisting of potassium carbonate (1.66 g, 12 mmol) and water (approximately 8.2 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction vial containing 3-acetamidobenzeneboronic acid (ASDI Incorporated, Newark, Del.; 107 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min. 1 M HCl (0.1 mL) was added to each vial, and the solution were passed through silica gel columns (1 g of silica), and washed with dimethylacetamide (2×1 mL). The solution was evaporated to dryness to give 2-(3′-acetylamino-biphenyl-4-yloxymethyl) -thiazole-4-carboxylic acid. Mass spectrum MH+=369.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]([CH2:24][CH2:25][CH3:26])=[N:6][N:5]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:29][N:28]=[N:27][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH2:24][CH2:25][CH3:26])=[N:6][N:5]=1
Reactant: CCCc1nnc(COC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nnc(COC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of 3-methoxymethyl-5-propyl-4-[(2'-cyanobiphenyl-4-yl)-methyl]-1,2,4-triazole (1.5 g, 4.33 mmol) in DMF (35 ml) was added sodium azide (NaN3, 0.84 g, 13 mmol) and ammonium chloride (NH4Cl, 0.69 g, 13 mmol). The mixture was stirred at 100° C. for four days whereupon an additional 0.3 g NaN3 and 0.23 g NH4Cl were added. Stirring was continued 2 days further at 100° C. The solvent was removed (rotary evaporation) and the residue was partitioned between ethyl acetate and water (100 ml ea). The organic phase was dried (MgSO4), filtered and concentrated to a viscous light brown oil (1.5 g) which was purified by flash chromatography on silica gel to give 350 mg (21%) of an off-white solid; m.p. 201°-205° C. (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([S:23][CH3:24])=[C:9]([C:21]#[N:22])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]([C:21]#[N:22])=[C:8]([S:23][CH3:24])[O:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:16][CH:15]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1oc(SC)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CSc1oc(C(=O)O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Yield: 29.7 %

Procedure:
Dissolve 3-(4-tert-butyl-phenyl)-4-cyano-5-methylsulfanyl-furan-2-carboxylic acid ethyl ester (110 mg, 0.32 mmol) in a solution of THF: MeOH: H2O (3:2:1, 5 ml). Add lithium hydroxide (80 mg, 3.3 mmol) to the mixture and stir the reaction at 60° C. for 30 minutes. Add 6N HCl until pH approx. 1 to obtain the desired white solid of the titled compound (30 mg, 30%): Mass spectrum (M−1)=314. EA, Calculated: C; 61.91, H; 5.68, N; 4.25. Found: C; 61.75, H; 5.42, N; 3.91.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])=[CH:6][C:3]=1[CH2:4]Br.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[CH:18]([N:21]([CH2:4][C:3]1[CH:6]=[C:7]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[C:8]([F:10])=[CH:9][C:2]=1[Cl:1])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CC(=O)N(C(C)=O)c1cc(CBr)c(Cl)cc1F
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N(C(C)=O)c1cc(CN(C(C)C)C(C)C)c(Cl)cc1F
Yield: 95.7 %

Procedure:
A mixture of 0.82 g (0.0025 mole) of 2-chloro-4-fluoro-5-diacetylaminobenzyl bromide, 0.28 g (0.0028 mole) of diisopropylamine, 0.39 g (0.0028 mole) of potassium carbonate, and 25 ml of acetonitrile was heated at reflux overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water. After being dried, the solvent was evaporated under reduced pressure, yielding 0.82 g of N,N-diisopropyl-2-chloro-4-fluoro-5-diacetylaminobenzylamine.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH:7]([C:18]([O:20][CH3:21])=[O:19])[CH2:6]1.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])C>O.C(Cl)(=O)OCC1C=CC=CC=1>[CH2:27]([O:26][C:23]([N:4]([CH2:3][CH:2]([CH3:22])[CH3:1])[CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:8][CH:7]([C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)=[O:25])[C:28]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:10]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C1CC(NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Agent: O=C(Cl)OCc1ccccc1
Solvent: O
Product: COC(=O)C1CC(N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-tert-Butyl 3-methyl 5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (13.7 g) was dissolved in ethyl acetate (250 ml)-1 M aqueous sodium hydroxide solution (55 ml)-water (200 ml), benzyl chlorocarbonate (7.5 ml) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-50:50) was concentrated under reduced pressure to give the object compound (9.87 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](=O)[CH3:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:24][C:23]1([CH2:22][O:21][C:20]2[CH:26]=[CH:27][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH2:2][C:1](=[O:3])[C:4]2[C:12](=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=2)[O:13]1
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(C(=O)O)ccc2O1
Yield: 88.7 %

Procedure:
A procedure similar to that described in Preparation 1 was repeated, except that 10 g of 3-acetyl-4-hydroxybenzoic acid, 13 g of 4-nitrophenoxyacetone, 7.9 g of pyrrolidine, 2.6 g of p-toluenesulfonic acid monohydrate and 150 ml of benzene were reacted, to afford 17.6 g of the title compound as pale brown crystals, melting at 227°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]([NH:32][CH2:33]C(O)=O)=[O:31])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C([N:52]([CH:56](C)C)C(C)C)C.C1C=CC2N([OH:68])N=NC=2C=1>O.CN(C=O)C>[C:56]([N:32]([CH3:33])[C:30]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)[CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:47][CH:46]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[O:31])(=[O:68])[NH2:52]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)NCC(=O)O)cn2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)C(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a DMF solution (1 ml) of [(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbonyl)-amino]-acetic acid (30 mg) obtained in Step A, ammonium chloride (5.0 mg), N-ethyldiisopropylamine (41 μl), HOBt (6.3 mg) and WSCI (13.4 mg) was added, followed by stirring at 80° C. for 3 hours. To this, water was added, and the resulting solid was filtered, to obtain a crude product of the desired compound (27 mg, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44].O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:43](=[O:45])[CH3:44])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(N)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(Oc2ccc(NC(C)=O)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To [3-(4-amino-2-{[methoxycarbonyl-((S)-1-methyl-2-phenyl-ethyl)-amino]-methyl}-phenoxy)-phenyl]-acetic acid ethyl ester (0.156 g, 0.33 mmol) and triethylamine (0.07 mL, 0.49 mmol) in CH2Cl2 (2 mL) was added acetyl chloride (0.02 mL, 0.33 mmol), and the reaction was stirred at room temperature for 2 minutes. LCMS analysis showed some starting material remained, so additional acetyl chloride (0.01 mL) was added, and the reaction was stirred for 30 minutes, until no starting material was seen by analytical LCMS. The mixture was worked-up with CH2Cl2 and H2O, and the organic layer was dried and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C#N)c2)c1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.64 mmol), 3-bromobenzonitrile (0.492 g, 2.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.054 g, 0.066 mmol), 1,4-dioxane (10 mL), and aqueous sodium carbonate (2 M, 2.64 mL, 5.27 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes using a microwave reactor. The resulting suspension was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated, and the organic layer was washed with water (10 mL) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carbonitrile. MS ESI calc'd. for C19H14F3N4 [M+H]+ 355, found 355.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[N:11]#[C:12]Br.C(=O)(O)[O-].[Na+]>O>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[NH:10][C:12]([NH2:11])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
The procedure used was similar to that reported in J. Med. Chem. 40:811–818, 1997. A solution of 1,2-diamino-4,5-difluorobenzene (500 mg, 3.47 mmol) in water (5 mL) was cooled to 0° C. and then treated with a solution of cyanogen bromide (0.83 mL, 4.16 mmol, 5 M in acetonitrile) and solid sodium bicarbonate (583 mg, 6.94 mmol). The solution was stirred at rt overnight and was then concentrated in vacuo. The dark residue was suspended in ethanol and heated at reflux for 15 minutes. The hot suspension was filtered, rinsing with hot ethanol, and the filtrate was concentrated in vacuo to afford 5,6-difluoro-1H-benzimidazol-2-amine (580 mg, 59%), which was used in the next step without further purification. LC-MS m/z 170.2 (MH+), ret. time 0.85 min; 1H NMR (300 MHz, DMSO-d6) δ 6.30 (br s, 2H), 7.06 (dd, 2H), 10.79 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1COCC1.CO>[CH3:24][O:14][C:13]([C@:9]1([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@]1(Cc2ccccc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirred solution of (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.23 g, 4.0 mmol) in THF (10 mL) and methanol (10 mL) at 0° C. under nitrogen was added TMS-diazomethane (5.0 mL of a 2.0 M solution in hexanes, 5.0 mmol) dropwise. The reaction mixture was warmed to ambient temperature then concentrated in vacuo to an oil (1.36 g). Purification by chromatography (silica, 5-15% EtOAc in hexanes) gave (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.03 g, 3.23 mmol, 81%) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>O1CCCC1>[OH:10][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c(C=O)n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(O)c(C(O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3-Hydroxy-6-methyl-pyridine-2-carbaldehyde (350 mg) was dissolved in tetrahydrofuran (13 ml) to prepare a solution which was brought to −78° C. Phenylmagnesium bromide (7.4 ml) was slowly added dropwise thereto, and the mixture was stirred at room temperature for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give 2-(hydroxyphenyl-methyl)-6-methyl-pyridin-3-ol (553 mg, yield 100%).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[NH2:14][C:15]1[C:20](C(O)=O)=[C:19]([CH3:24])[N:18]=[C:17]2[S:25][C:26]([Br:35])=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=3)[C:16]=12>C(Cl)Cl>[Br:35][C:26]1[S:25][C:17]2[N:18]=[C:19]([CH3:24])[CH:20]=[C:15]([NH2:14])[C:16]=2[C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1
Reactant: Cc1nc2sc(Br)c(-c3cccc(Br)c3)c2c(N)c1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(N)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Temperature: 200 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
Diphenyl ether (20 mL, 126 mmol) was added to 4-amino-2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylic acid (Description 48) (1.861 g, 4.21 mmol). The mixture was heated to 200° C. and stirred at 200° C. for 4 h. The mixture cooled to RT and was stirred overnight at RT. The mixture was then diluted with DCM and purified by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (1.0 g). LCMS (A) m/z: 399 [M+1]+, Rt 0.94 min (acidic).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13].[CH3:34][CH2:35][C:36](=[O:39])[CH2:37][CH3:38]>O1CCCC1>[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:36]([CH2:37][CH3:38])([OH:39])[CH2:35][CH3:34])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C)CC
Reaction time: 3 h
Yield: 65.8 %

Procedure:
A 2.5 M solution of n-butyllithium in hexane (14.7 mL, 36.73 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 4.28 g, 14.69 mmol) in tetrahydrofuran (92 mL) at −78° C. Pentan-3-one (4.85 mL, 44.07 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for three hours and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and a 1 N hydrochloric acid aqueous solution was added to adjust the pH to about 7. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=6/1) to give the title compound (3.66 g, 62%).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([NH:7][CH2:8][CH2:9][CH2:10][OH:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: NCCCO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(NCCCO)c1cccc(Br)c1

Procedure:
3-Bromo-N-(3-hydroxy-propyl)-benzenesulfonamide (266 mg) obtained from the reaction of pyridine, 3-aminopropanol and 3-bromobenzenesulfonyl chloride in acetonitrile was left to act in di-tert-butyl carbonate (226 mg) and acetonitrile (5 ml) in the presence of DMAP (10 mg), to obtain 3-bromo-N-Boc-N-(3-hydroxy-propyl)-benzenesulfonamide as a colorless oil (267 mg, 72%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[CH:14]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Product: Cc1ccc(NC(=O)c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Yield: 99 %

Procedure:
Using an analogous procedure to that described in Example 37, 4-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)benzamide to give the title compound in 99% yield; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 4.84 (s, 2H), 7.22 (d, 1H), 7.54 (m, 6H), 7.84 (s, 1H), 7.96 (m, 4H), 9.92 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M−H− 377.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:17][CH2:18][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:20][CH2:21]4)[C:5]=3[C:4]1=2)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (691 mg, 1.59 mmol, 1.00 equiv) in 4 mL of DCM was added MsCl (366 mg, 3.18 mmol, 2.00 equiv) and triethylamine (643 mg, 6.35 mmol, 4.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and quenched with water. The resulting solution was extracted with 3×30 mL of DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum afford tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (900 mg, crude) as a red oil. MS: m/z 512 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Br-:12].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:12][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:11])[CH3:1])[CH:7]=[O:8]
Reactant: [Br-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN(C)c1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4-(dimethylamino)-benzaldehyde (10.0 g, 67.03 mmol) in dichloromethane (250 mL) was added pyridinium tribromide (21.4 g, 67.03 mmol). The reaction mixture was stirred at room temperature overnight. The solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Choromatography on silica gel (15% EtOAc in hexane) afforded 14.06 g of 3-bromo-4-(dimethylamino)-benzaldehyde (92%).