Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]3[CH2:16][CH2:15][C:14]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:13][C:12]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([N:11]4[CH2:16][CH2:15][C:14]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[O:13][C:12]4=[O:27])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][N:31]=1
Reactant: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(Br)cc3)CC2)C(=O)O1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccnc(OC)c4)cc3)CC2)C(=O)O1
Temperature: 130 °C
Yield: 74.7 %

Procedure:
3-(1-(4-bromophenyl)cyclopropyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (33 mg, 0.078 mmol), 2-methoxypyridine-4-boronic acid pinacol ester (27 mg, 1.5 equiv), Pd(dppf)Cl2 (6 mg, 10% mol), 2M aq Na2CO3 (1 mL), 1,4-dioxane (2.5 mL) were mixed in a tube for microwave oven. The tube was evacuated and refilled with nitrogen gas (3×) and heated in the microwave oven for 120 min at 130° C. LC-MS found the reaction was complete. The mixture was diluted with EtOAc (10 mL), washed with water (4 mL) and brine (3 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 4-g silica gel column, eluted with a 10˜50% EtOAc in hexanes gradient, to afford 3-(1-(4-(2-methoxypyridin-4-yl)phenyl)cyclopropyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (26.5 mg, 75%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O-:17].[Na+]>CO>[NH2:1][C:2]1[C:6]2[C:7]([O:17][CH3:16])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ccnc(Cl)c2c1N
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2ccnc(OC)c2c1N
Yield: 94.2 %

Procedure:
The product from Example 48A (1.2 g, 4.9 mmol) and sodium methoxide (1.0 g, 19 mmol) were refluxed in 30 mL MeOH for 6 h. The reaction was partitioned between water and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated. Silica gel chromatography (CH2Cl2) yielded 1.1 g (78%) of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.05 (s, 3H), 6.96 (bs, 2H), 7.47 (d, J=6 Hz, 1H), 8.07 (d, J=6 Hz, 1H); MS (DCI(NH3)) m/e 239 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[C:18]([C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22])#[N:19]>>[C:18]([C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)#[N:19]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1ccc(C#N)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-cyano-5-methylaniline (38 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (8 mg, 12%). 1H NMR (CDCl3): 9.62–9.61 (m, 1H), 8.75–8.69 (m, 2H), 8.08 (s, 1H), 7.62 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.46–7.41 (m, 1H), 7.12 (dd, J=0.9, 8.1 Hz, 1H), 7.00 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]([C:12](Cl)=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].CCOCC>C1COCC1>[C:15]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:13])=[CH:10][CH:11]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Glycine (5 mmol) was reacted with 4-biphenylcarbonyl chloride (about 5 mmol) in the presence of 1N NaOH solution (10 ml), ether (21 ml) and THF (2 ml) using the procedure described in Example 5. Most of the product precipitated as a solid on acidification of the aqueous layer during the work up. This was found to be quite insoluble in CHCl3 and EtOAc. It was largely dissolved in CH3CN (~35 ml) and filtered to remove insoluble material. Crystalline acid (0.81 g, 63%) was deposited on cooling, m.p. 207°-218° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([F:29])[CH2:20]OS(C(F)(F)F)(=O)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[C:9]([O:10][CH2:20][C:19]([F:30])([F:29])[F:18])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To 2,6-dichloro-3-hydroxy-benzaldehyde (114, 2.06 g, 0.0108 mol) in N-methylpyrrolidinone (25.0 mL) were added cesium carbonate (7.02 g, 0.0215 mol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.50 g, 0.0108 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 90 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 100% ethyl acetate in hexane to give a colorless oil (115, 1.00 g, 34.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CCO.O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][CH2:29][OH:30])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCCO)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
1-{4′-[4-(2-Carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.336 g, 0.8 mmol) and triethylamine (0.145 mL, 1.04 mmol) were dissolved in THF (6.6 mL) under N2 atmosphere and cooled to 0° C. Isobutyl chloroformate (0.126 mL, 0.96 mmol) was added and the reaction stirred for 40 minutes and was then filtered, rinsing with dioxane and THF, and the filtrate was collected and concentrated. The crude material was dissolved in THF (10 mL), H2O (4.4 mL), and EtOH (1.9 mL), and then sodium borohydride (0.176 g, 4.6 mmol) was added. The reaction was heated to 50° C. for five hours then cooled and submitted to standard aqueous workup. The residue was purified on silica gel (0-80% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C1CCNC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol), Pyrrolidine (85 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 294 (31.3 mg, yield: 5.9%). 1HNMR (DMSO-d6, 400 MHz): δ8.81 (s, 1H), 8.38 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98-7.97 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.48 (t, J=4.4 Hz, 1H), 7.26 (s, 1H), 6.60 (d, J=8.8 Hz, 1H), 4.38 (s, 2H), 3.54 (s, 3H), 3.22 (s, 2H), 2.07 (s, 4H). ESI-MS: m/z=529 [M+H+]
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[N:4]([CH3:13])[N:3]=1
Reactant: CC1(C)CCc2c(I)n[nH]c2C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2c1CC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a solution of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (919 mg, 3.33 mmol) in THF (8 mL) at 0° C. was added KOt-Bu (523 mg, 4.66 mmol). The reaction mixture was stirred at 0° C. for 30 min then iodomethane (0.29 mL, 4.66 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The residue was absorbed onto SiO2 and purified by chromatography with 10% to 20% EtOAc/hexanes to afford 523 mg (54%) of 3-iodo-1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.72 (s, 3H), 2.33 (t, J=6.4 Hz, 2H), 2.29 (s, 2H), 1.51 (t, J=6.4 Hz, 2H), 1.02 (s, 6H). Also isolated 160 mg (17%) of 3-iodo-2,6,6-trimethyl-4,5,6,7-tetrahydro-2H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.87 (s, 3H), 2.41 (s, 2H), 2.36 (t, J=6.6 Hz, 2H), 1.54 (t, J=6.6 Hz, 2H), 1.00 (s, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7](O)[CH3:8])[CH2:3][CH2:2]1.C[O-].[Na+].COC1C=CC(O)=CC=1.[C:22]([O:27]C)(=[O:26])[C:23]([CH3:25])=[CH2:24]>>[C:22]([O:27][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)OC
Reactant: CC(O)N1CCOCC1
Agent: COc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Product: C=C(C)C(=O)OCCN1CCOCC1

Procedure:
A 1000 ml resin kettle was equipped with a still head, air bubbler, and thermometer. The kettle was placed in a regulated water bath, set at 80°. 750 ml methyl methacrylate was added to the kettle followed by a solution containing 250 g morpholinoethanol, 5.0 g sodium methoxide and 0.5 g p-methoxyphenol. During the 120 minute reaction time, air was bubbled slowly through the vigorously stirred solution. After 30 and 60 minutes, 5.0 g sodium methoxide was added. At the end of the reaction time, the mixture was cooled and neutralized with 17.0 g glacial acetic acid.
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:33][C:34]1[N:39]=[C:38]([N:40]([CH3:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[C:36]([C:48]2[N:52]=[C:51]([N:53]3[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]3)[O:50][N:49]=2)[N:35]=1>O1CCOCC1.C(Cl)Cl>[CH3:47][N:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]1[N:39]=[C:34]([NH2:33])[N:35]=[C:36]([C:48]2[N:52]=[C:51]([N:53]3[CH2:54][CH2:55][C:56](=[CH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:57][CH2:58]3)[O:50][N:49]=2)[N:37]=1
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(=O)CC3)n2)n1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(=CCC(F)(F)F)CC3)n2)n1
Reaction time: 0.17 h
Yield: 11.9 %

Procedure:
To a solution of triphenyl-(3,3,3-trifluoro-propyl)-phosphonium iodide (146 mg, 0.30 mmol) in anhydrous dioxane (10 mL) at 0 C under nitrogen was added potassium tert-butoxide (34 mg, 0.3 mmol) portion-wise. The suspension was stirred for 10 min at 0 C and then added drop-wise to a solution of 1-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-piperidin-4-one (Intermediate 131, 55 mg, 0.150 mmol) in anhydrous dioxane (10 mL). The resulting reaction mixture was stirred at room temperature for 16 h and evaporated to dryness. The solid obtained was dissolved in DCM (25 mL) and washed with water (25 mL), a saturated ammonium chloride aq. solution (25 mL) and brine (25 mL). The organic phase was dried over magnesium sulfate, evaporated to dryness and purified by preparative HPLC-MS (Method B) to afford the title compound as an off-white solid (8 mg, 12%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH2:15]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc(CC2CCCCN2)cc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Brc1ccc(CC2CCCCN2Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a 100 mL round-bottomed flask equipped with N2 inlet were added 250 mg (0.984 mmol) 2-(4-bromobenzyl)-piperidine (prepared as described in Tetrahedron Letters, 7, 631 (1977)), 110 uL (1.08 mmol) benzaldehyde, 7 mL methanol, 74 mg (1.18 mmol) sodium cyanoborohydride, and a few drops of acetic acid. The reaction was stirred at room temperature, followed by additional benzaldehyde, sodium cyanoborohydride, and acetic acid, for a total of 16 hours then poured into dilute aqueous sodium bicarbonate solution, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant, and the product further purified by conversion to the hydrochloride salt in ether followed by basification using aqueous sodium hydroxide solution to afford 175 mg (52%) of an oil.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([NH2:6])=O.[CH2:13](N(CC)CC)C.ClC(OC)=O>C(Cl)Cl>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: NC(=O)c1ccccc1C(=O)O
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1C#N
Reaction time: 16 h

Procedure:
Phthalamic acid (240 g, 1.37 moles) in methylenechloride (1.7 l) was stirred and cooled to <5° in an ice bath. Triethylamine (244 ml, 176 g, 1.74 moles) was added and a clear solution was obtained. Methyl chloroformate (200 g, 163 ml, 2.1 moles) was added at such a rate that the temperature did not exceed 5°. As the addition continued, triethylamine hydrochloride precipitated and carbon dioxide was evolved. On completion of the addition, the ice bath was removed and stirring was continued for 12-20 hrs. at room temperature. Triethylamine hydrochloride was removed by filtration and the methylene chloride evaporated. The residue was dissolved in ether (2 l), and this ether solution washed with water, dried over anhydrous sodium sulfate and evaporated. Distillation under reduced pressure gave methyl 2-cyanobenzoate, b.p. 125° at 2.5 mm, 215 g (97%), a solid at room temperature, M.P. 45°-6°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26])=[O:9]
Reactant: CNC(=O)c1cccc(OCc2ccc(Cl)cc2C(=O)O)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: CNC(=O)c1cccc(OCc2ccc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-({3-[(methylamino)carbonyl]phenoxy}methyl)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 1):
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1C(=O)O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of 2-tert-butylbenzoic acid (1.00 g) in THF (20 mL) was added 1.0M borane THF complex THF solution (16.8 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (942 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([S:17]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH3:21])(=[O:19])=[O:18])=[C:4]([F:30])[CH:3]=1.BrC1[C:33]([Cl:39])=[CH:34][C:35]([CH3:38])=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:37]=[N:36][C:35]([CH3:38])=[CH:34][C:33]=2[Cl:39])=[CH:6][C:5]([S:17]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH3:21])(=[O:19])=[O:18])=[C:4]([F:30])[CH:3]=1
Reactant: Cc1cc(Cl)c(Br)cn1
Reactant: COc1ccccc1N(C)S(=O)(=O)c1cc(C2OC(C)(C)C(C)(C)O2)c(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1N(C)S(=O)(=O)c1cc(-c2cnc(C)cc2Cl)c(Cl)cc1F
Temperature: 85 °C

Procedure:
4-Chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-5-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-benzenesulfonamide (57 mg, 0.125 mmol), 5-bromo-4-chloro-2-methyl-pyridine (21 mg, 0.1 mmol), Pd(Ph3P)4 (12 mg, 0.01 mmol), K2CO3 (69 mg, 0.5 mmol) in a mixture of dioxane (1.5 mL) and water (0.15 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and heated at 85° C. for 14 hrs. After the filtration, the mixture was purified by prep. LCMS to afford 4-chloro-5-(4-chloro-6-methyl-pyridin-3-yl)-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzenesulfonamide 3-1. MS: 454.7 (M+H)+; tR=7.77 min (method 2). NMR (CDCl3), δ, 8.350 (1H, s), 7.549 (1H, d, J=6.9 Hz), 7.257-7.436 (5H, m), 6.932 (1H, m), 6.817 (1H, m), 3.513 (3H, s), 3.389 (3H, d, J=2.1 Hz), 2.656 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:13]([O:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][O:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:10])[OH:8])[OH:6])=[O:4])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](O)[C@H](O)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 29.8 %

Procedure:
To a solution of D-fructose (10 g, 55.5 mmole) in pyridine (40 ML) and chloroform (25 mL) was added trityl-chloride (35 g, 126.3 mmole) and the mixture was stirred at 25° for 2 days, another 5 g of trityl chloride was added and stirring was continued for 2 days. Solvent was removed under reduced pressure and the residue was extracted with chloroform, washed with aqueous saturated cupric sulfate solution, brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography [chlorofm-methanol (100:1)] gave 1,6-Di-O-trityl-D-fructose (11 g, 30%). This compound was identified by its specific rotation and by NMR and Mass spectrometry.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[Br:8][C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15](Cl)=[N:14][C:13]=12.C(N(C(C)C)C(C)C)C.CCOC(C)=O>CN(C=O)C>[Br:8][C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15]([NH:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4])=[N:14][C:13]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: CC(C)[C@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CO)Nc1ccn2ncc(Br)c2n1
Temperature: 100 °C
Yield: 97.2 %

Procedure:
To a solution of (S)-2-amino-3-methylbutan-1-ol (3.3 g, 32 mmol) in DMF was added 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (2.5 g, 11 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.2 g, 32 mmol) and the reaction was heated to 100° C. for 4 hours. The reaction mixture was poured into EtOAc and washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield (S)-2-(3-bromopyrazolo[1,5-a]pyrimidin-5-ylamino)-3-methylbutan-1-ol (3.2 g, 99%). LCMS (APCI+) m/z 299, 301 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].Cl.[OH-].[Na+]>C(O)(=O)C.CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:4]([OH:5])[CH3:3]
Reactant: CC(=O)c1ccccn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1ccccn1
Reaction time: 4 h

Procedure:
To a solution of 110 g. of sodium borohydride in 1250 ml. of methanol at 0°C. is added 350 g. of 2-pyridyl methyl ketone in 300 ml. of methanol with stirring. After stirring for 4 hours at 0°-5°C., glacial acetic acid is cautiously added dropwise, followed by ice and concentrated hydrochloric acid. The acidic solution is made basic with aqueous sodium hydroxide and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, concentrated and distilled to give 1-(2-pyridyl)ethanol.