Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[N:37]2[CH2:38][CH2:39][NH:40][CH2:41][C:36]2=[CH:35][N:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[O:13]=[C:11]([N:40]1[CH2:39][CH2:38][N:37]2[C:33]([C:32]([F:43])([F:31])[F:42])=[N:34][CH:35]=[C:36]2[CH2:41]1)[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23]
Reactant: FC(F)(F)c1ncc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(cnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane. After stirring for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted for 2 hours and then concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography with system B as eluant to obtain the title compound tert-Butyl (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamate 1m (20.0 g, yield 88%) as a white solid. 1H NMR (400 MHz, CD3OD, ppm): δ 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (m, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].O1CCOCC1.Br.Br[CH2:23][C:24]([C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=1)=O>O>[F:35][C:32]([F:33])([F:34])[C:31]1[C:26]([C:24]2[N:1]=[C:2]3[N:3]=[CH:4][CH:5]=[C:6]([NH2:9])[C:7]3=[N:8][CH:23]=2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(CBr)c1ncccc1C(F)(F)F
Reactant: Nc1ccnc(N)c1N
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccnc2nc(-c3ncccc3C(F)(F)F)cnc12

Procedure:
Dissolve 2,3,4-triaminopyridine (2.5 mmol) in water (20 mL). Add NaHCO3 (0.63 g, 7.5 mmol), dioxane (10 mL), and 2-bromo-1-(3-trifluoromethyl-pyridin-2-yl)-ethanone hydrobromide (0.5 g) and stir at 100° C. for 2 hours. Cool the mixture and extract with EtOAc (4×10 mL). Wash the combined organic extracts with brine and dry over Na2SO4. Purify the residue by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: N#Cc1cc(Br)ccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Product: Cc1cc(-c2ccnc(C#N)c2)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-cyanopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a off-white solid, MS (ISP): m/e=336.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[C:20]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Yield: 77.1 %

Procedure:
A mixture of 2-methoxy-4-nitroaniline (2.23 g, 13.3 mmol), triethylamine (2.00 ml, 14.6 mmol) and benzoyl chloride (1.70 ml, 14.6 mmol) were stirred in toluene (50 ml) for 24 hours under an inert atmosphere at ambient temperature. The solid was collected by suction filtration and washed with toluene (3×50 ml) and diethyl ether (50 ml). Purification of the crude product by flash chromatography on silica gel, eluting with dichloromethane, yielded N-benzoyl 2-methoxy-4-nitroaniline (2.79 g, 77% yield) as a white solid:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:27])=[C:12]([N:16]2[CH2:19][CH:18]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Br[C:29]1[CH:30]=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:33][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[Cl-].[NH4+]>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.C(Cl)(Cl)Cl.C1COCC1.O1CCOCC1>[F:27][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:17][CH:18]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:33][CH:34]=3)[CH2:25][CH2:26]2)[CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(OC3CCNCC3)C2)c1F
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCC(OC3CN(c4cccc(CO)c4F)C3)CC2)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
4-({1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}oxy)piperidine (250 mg) and dioxane (7 ml) were mixed, and methyl 5-bromopyridine-2-carboxylate (170 mg), palladium acetate (II)(15 mg), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (60 mg), and tripotassium phosphate (400 mg) were added thereto, followed by stirring 100° C. for 48 hours. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with THF (5 ml), and a 1.0M TBAF/THF solution (0.63 ml) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain methyl 5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridine-2-c arboxylate (92 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[O-]S([O-])(=O)=O.[Mg+2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH2:22]([NH:7][C@@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:4][CH2:2][CH3:3])=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NCc1ccccc1
Yield: 60.8 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-phenylalanine ethyl ester hydrochloride (2 gm, 8.7 mmol), THF (25 mL), MgSO4 (1.78 gm, 14.79 mmol), benzaldehyde (1.77 mL, 17.4 mmol), Et3N (1.21 mL, 8.7 mmol), sodium borohydride (658 mg, 17.4 mmol), and methanol (30 mL) to give 11c (1.5 gm, 61%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 1.19 (3H, t, J=7.08 Hz), 1.88-2.1 (1H, bs), 3.01 (2H, dd, J=0.97, 7.81 Hz), 3.56 (1H, t, J=6.83 Hz), 3.69 (1H, d, J=13.42 Hz), 3.85 (1H, d, J=13.18 Hz), 4.13 (2H, q, J=7.32 Hz), 7.18-7.22 (2H, m), 7.23-7.33 (8H, m). ESI-MS: 284.0 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH2:26]>C(O)C>[CH3:31][C:30]([CH3:33])([O:29][C:27]([NH:25][N:26]=[C:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH2:19][CH2:20]1)=[O:28])[CH3:32]
Reactant: O=C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
A mixture of 16.0 g (0.05 mol) of 1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone, 7.25 g (0.055 mol) of tert. butyl hydrazinoformate and 250 ml of ethanol was refluxed for 1 hour. The solvent was distilled off in vacuo, the oily residue remaining was triturated with diethylether. The crystalline precipitate thus formed was suction filtered and washed with a little diethylether. After the product had been dried in vacuo 21.7 g (99.7% of theory) of colourless crystals were obtained, m.p. 156-158° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([NH2:21])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(CC)C(C)C)(C)C>C(O)C.CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([NH:21][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cccc2nc(C(C)N)c(-c3cc(F)cc(F)c3)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)cc(F)c3)n12
Yield: 58.1 %

Procedure:
A solution of 1-[3-(3,5-difluorophenyl)-5-methylimidazo[1,2-a]pyridin-2-yl]ethanamine (40 mg, 0.14 mmol), 6-bromo-9H-purine [Aldrich, 104981] (33 mg, 0.17 mmol), and N,N-diisopropylethylamine (29 μL, 0.17 mmol) in ethanol (1.6 mL) was heated at 90° C. for 18 h. The reaction mixture was diluted with methanol and purified by preparative LCMS to give the desired product (33 mg, 58%) as a white solid. LCMS for C21H18F2N7 (M+H)+: m/z=406.1. 1H NMR (400 MHz, CD3OD): δ 8.12 (s, 1 H), 8.03 (br s, 1 H), 7.49 (d, J=9.0 Hz, 1 H), 7.25 (dd, J=9.0, 6.8 Hz, 1 H), 7.21-7.18 (m, 1 H), 7.00-6.94 (m, 2 H), 6.66 (d, J=6.8 Hz, 1 H), 5.44 (br s, 1 H), 2.15 (s, 3 H), 1.69 (d, J=7.0 Hz, 3 H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([CH2:18][OH:19])[CH:3]=1.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd].C(OCC)(=O)C>[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]=[C:6]3[N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[N:9]=[C:10]([CH3:11])[C:5]3=[C:4]([CH2:18][OH:19])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(Br)cc(CO)c12
Reactant: COCOc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COCOc1ccc(-c2cc(CO)c3c(C)nn(C4CCCCO4)c3n2)cc1
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 103.2 %

Procedure:
To a degassed mixture of 141 mg [6-Bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanol, 95 mg 4-(methoxymethoxy)phenylboronic acid and 65 mg potassium carbonate in DME/water (v/v=2/1, 2.3 mL) at r.t. and under Ar-atmosphere 6 mg palladium(0) bis(tri-tert-butylphosphine) was added and the mixture was stirred at 85° C. for 40 min in a microwave reactor. Then 6 mg palladium(0) bis(tri-tert-butylphosphine) and 95 mg 4-(methoxymethoxy)phenylboronic acid were added and the mixture was stirred at 100° C. for 20 min. To the mixture water and ethyl acetate were added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated in vacuo and the residue was triturated with ethyl acetate. The resulting solid was isolated by filtration. 171 mg (100%) of the title compound were obtained.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([CH3:17])[N:4]=1.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>N1C=CC=CC=1>[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([CH3:17])[N:4]=1
Reactant: CSc1nc(C)c(Cc2cccnc2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: c1ccncc1
Product: Cc1nc(NCCSCc2nc[nH]c2C)[nH]c(=O)c1Cc1cccnc1

Procedure:
Treatment of 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine in refluxing pyridine for 25 hours, followed by evaporation of the mixture and chromatographic purification of the residue on silica gel (eluting with chloroform/methanol 5:1) gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 128°-131°.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3](=[O:33])[CH:4]([NH:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH3:30])[NH:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20]C(OC(C)(C)C)=O)[CH:5]([CH3:7])[CH3:6].Cl>C(OCC)(=O)C>[F:35][C:2]([F:1])([F:34])[C:3](=[O:33])[CH:4]([NH:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH3:30])[NH:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH2:20])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)N)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
A solution of 1,1,1-Trifluoro-3[(N-tert-butyloxycarbonylalanyl)alanyl-prolylamino]-4-methylpentan-2-one (180 mg, 0.35 mmol) in ethyl acetate (50 ml) was cooled to 0° C. and treated with hydrogen chloride gas for 5 min. The reaction mixture was stirred at 0° C. for 1.5 hr, followed by removal of solvent in vacuo. 1,1,1-Trifluoro-3-[alanylalanylprolylamino]-4-methylpentan-2-one (151 mg, 0.34 mmol) was obtained in 96% yield and was used for subsequent reactions without purification.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:8]([O:1][CH2:8][C:7]1[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=1)[C:7]1[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1
Yield: 82 %

Procedure:
Compound 11a (Rb═H, 2.0 g, 6.34 mmol) was dissolved in DCM/water, 2/1, v/v (30 ml) and to this solution was added sodium hydroxide (2N, 10 ml). To this mixture was added tetrabutylammonium bromide (0.2 g, 0.63 mmol, 0.1 eq) and 4-chlorobenzyl bromide (1.43 g, 6.98 mmol, 1.1 eg). The mixture was stirred for 16 hrs at room temperature after which time TLC analysis (100% DCM, Rf 0.55) showed complete reaction. The mixture was diluted with DCM (15 ml/mmol), the layers were separated and the water layer was extracted with DCM. The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/petroleum ether, 3/1 to 1/0, v/v) to give compound 12 (Ra=4Cl, Rb═H, 2.3 g, 82%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9H); 2.75 (bs, 2H); 3.75 (bs, 2H); 4.35 (bs, 2H); 5.05 (s, 2H); 6.4 (s, 1H), 6.94 (d, 1H); 7.30-755 (m, 7H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][C:8]=1[C:12]1([CH3:17])[O:16]CCO1.[C:18](=[O:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C(OCC)C.O>[C:12]([C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:18]([OH:20])=[O:19])(=[O:16])[CH3:17]
Reactant: O=C=O
Reactant: CC1(c2occc2Br)OCCO1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1occc1C(=O)O
Reaction time: 0.5 h

Procedure:
At 0°, a solution of anhydrous ferric chloride (2.7 g, 17.0 mmol) in 50 ml of nitromethane is added portionwise with stirring over a period of 5 hours to a mixture of 3-bromofuran (25.0 g, 170.0 mmol) and acetic anhydride (20.4 g, 200.0 mmol) in 50 ml of nitromethane. After addition is completed, the resulting mixture is stirred at RT for 17 hours and is then evaporated in vacuo. The residue is taken up in 200 ml of diethyl ether, treated with 3.0 g of activated charcoal and filtered. The filtrate is washed with 5% sodium bicarbonate and dried and the solvent is removed by rotoevaporation to give, after purification, 2-acetyl-3-bromofuran. A well-stirred mixture of 2-acetyl-3-bromofuran (13.7 g, 72.0 mmol), ethylene glycol (5.9 g, 94.0 mmol), p-toluenesulfonic acid (p-TSOH; 20 mg) and benzene (50 ml) is refluxed for 9 hours, after which additional ethylene glycol (1.8 g, 29.0 mmol) and p-TSOH (5 mg) is added and the refluxing is continued a further 16 hours. The reaction mixture is then washed with sat. sodium bicarbonate and with water and is dried. The solvent is removed by rotoevaporation to give 2-(3-bromo-2-furyl)-2-methyl-1,3-dioxolane. To a solution of 1.6M butyllithium in hexane (38 ml) and dry diethylether (40 ml), under N2, is added dropwise with stirring a solution of the above dioxolane (11.18 g, 48.0 mmol) in 40 ml of ether, keeping the temperature below -68°. After addition is completed, the mixture is stirred for 30 min. at -70°, and then a slurry of CO2 (50.0 g) in 100 ml of dry diethyl ether is added. The mixture is kept at -65° for 15 min. and is then allowed to warm to 10°. Water is added, followed by 10% sodium carbonate. The phases are separated and the organic phase is extracted. The combined aqueous phases are acidified with conc. HCl and extracted with ether. The organic phases are combined and dried and the solvent is removed by rotoevaporation. The resulting product is suspended in 5% HCl (85 ml) and stirred at RT for 2 hours, then extracted with ether and the combined ether phases are dried and evaporated to dryness. The crude product is purified to give 2-acetyl-3-furancarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (2 g, 11.3 mmol) was dissolved in CH2Cl2 (57 ml) and cooled to 0° C. in an ice bath. The mixture was treated with Et3N (3 ml, 22.6 mmol) followed by the addition of Tf2O (1.9 ml, 11.3 mmol). The reaction mixture was warmed to room temp. and stirred for 4 hours. Saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layers were combined and dried (MgSO4), filtered, and concentrated. The residue was then purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:23])N(OC)C)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18](=[O:23])[CH3:25])[CH2:16][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 500 mL flask was charged with 15.2 g (45.4 mmol) trans-[4-(methoxy-methyl-carbamoyl)-cyclohexylmethyl]-carbamic acid benzyl ester and 350 mL anhydrous THF. The soluton was cooled to 0° C. then 33.3 mL (99.9 mmol) 3M CH3MgCl was added dropwise over 10 minutes. The reaction mixture was then stirred for 1 hour at 0° C. then quenched with 20 mL 2N acetic acid and poured into 300 mL water. The aqueous was extracted with ethyl acetate (3×200 mL) and the combined organics were washed with 0.5M HCl (1×100 mL), water (1×100 mL), brine (1×100 mL), dried over Na2SO4 and concentrated to a solid. The solid was recrystalized from IPE and filtered to give 5.5 g of a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH:13]([OH:16])[CH:14]=[CH2:15].[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C>N1C=CC=CC=1>[C:17]([O:16][CH:13]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:14]=[CH2:15])(=[O:19])[CH3:18]
Reactant: C=CC(O)C#CCCCCCCCCCCl
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: C=CC(C#CCCCCCCCCCCl)OC(C)=O
Yield: 55.7 %

Procedure:
To the crude alcohol from Step (D) supra., there is added 2.34 kg. (29.6 moles) of dry pyridine. Under a blanket of nitrogen gas, 6 kg. (59.2 moles) of acetic anhydride is added at room temperature over a 6 hour period. After stirring several additional hours, a sample is pulled and analyzed on a 6' carbowax column for loss of alcohol and appearance of the desired acetate. After completion of the reaction, the crude product is transferred to a distillation apparatus where the excess acetic anhydride and residual pyridine are removed under vacuum. Finally, the product is flash distilled through a thin film evaporator, the first pass removing residual lights and unreacted 11-chloro-1-undecyne from Step (D), supra., and the second pass to flash the product off higher boiling residues at 170° C./3 mm Hg. This yields 15.3 kg. (53.8 moles) of the acetate which is sufficiently pure to carry on to the next step (yield is 55.7% based on 11-chloro-1-undecyne in Step (D) supra.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Cl:13][C:10]1[S:9][C:8]([C:6]2[N:5]=[C:4]([CH3:14])[N:3]=[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=3)[N:7]=2)=[CH:12][CH:11]=1
Reactant: Cc1nc(Cl)nc(-c2ccc(Cl)s2)n1
Reactant: Nc1ccc(F)cc1
Product: Cc1nc(Nc2ccc(F)cc2)nc(-c2ccc(Cl)s2)n1
Yield: 24 %

Procedure:
4-(5-chlorothiophen-2-yl)-N-(4-fluorophenyl)-6-methyl-1,3,5-triazin-2-amine was prepared using 2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine and 4-fluoroaniline by the method described for Step 3 of EXAMPLE 1 (13 mg, 24% yield). MW=320.77. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=4.2 Hz, 1H), 7.64 (dd, J=9, 4.8 Hz, 2H), 7.11 (t, J=8.7 Hz, 2H), 7.01 (d, J=4.2 Hz, 1H), 2.55 (s, 3H).