Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NN[C:7]=2[CH:6]=CC=1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.Cl.[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([OH:54])=O)=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40].N[C@H](CC)CO.Cl>C1COCC1.CCCCCCC.C(OCC)(=O)C>[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([NH:10][C@@H:11]([CH2:3][OH:2])[CH2:7][CH3:6])=[O:54])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: CC[C@@H](N)CO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Hydroxybenzotriazole hydrate (43.1 mg, 0.28 mmol), N-ethyldiisopropylamine (241 μL, 1.38 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (54.0 mg, 0.28 mmol) were added at 0° C. to a solution 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and [R]-(−)-2-amino-1-butanol (32.4 μL, 0.33 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature overnight. Addition of aqueous hydrochloric acid (1 N, 10 mL), extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=0:1 to 1:0) afforded the title compound (45 mg, 38%) as a white solid. MS: m/e=434.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:10][CH2:9]1)=[CH:6][CH3:7])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7])[CH3:2]
Reactant: CC=C(C(=O)OCC)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C(CC)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 134 %

Procedure:
23 g of this ester dissolved in 200 ml of ethanol are hydrogenated under 60 lbs of pressure in the presence of Raney nickel. The theoretical quantity of hydrogen is absorbed in 3 hours. After filtration of the catalyst, the filtrate is concentrated in vacuo and the residue is distilled. In this manner 31 g of 4-(3-trifluoromethylphenyl)piperazin-1-ylbutanoic acid ethyl ester are obtained, b.p.0.3 mm Hg =146°-147° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[C:11]#[CH:12].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[CH2:10]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:20][CH:21]=1)[C:11]#[CH:12]
Reactant: NCCCCCC(=O)O
Reactant: C#CCOc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1ccc(CNCCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 6-aminohexanoic acid (2.62 g, 20 mmol), 4-(prop-2-yn-1-yloxy)benzaldehyde (0.80 g, 5.0 mmol) and acetic acid (0.50 mL) in DCE (50 mL) was heated at 80° C. for 60 min. The reaction mixture was cooled to 0° C., and treated with NaBH(OAc)3 (2.11 g, 10 mmol). The reaction was stirred at room temperature for 12 hours and decomposed with water and then extracted with DCM. The organic layer was dried and concentrated under reduced pressure to give a residue, which was purified using a Biotage SP4 and gradient elution of 5-50% methanol in DCM. The yield of the target compound 6-((4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid was 62% (0.856 g). 1H NMR (400 MHz, DMSO-d6): δ 7.19 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.71 (s, 2H), 3.56 (s, 2H), 3.49 (s, 1H), 2.39 (t, J=7.0 Hz, 2H), 2.00 (t, J=7.2 Hz, 2H), 1.41-1.19 (m, 6H); MS (ESI), 276.1 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C([O-])(O)=O.[Na+]>C(#N)C>[OH:17][C:16]1[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1cccnc1C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCC(c2ncccc2O)CC1

Procedure:
2-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyridin-3-ol (1.30 g, 5.52 mmol) as prepared in the previous step was treated with 1N HCl (˜16 mL) in acetonitrile (100 mL) at room temperature for 4 hours. The reaction was neutralized with saturated NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:43])[CH2:33][NH:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=2)[CH2:27]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:42][C:37]1[CH:36]=[C:35]([NH:34][CH2:33][C:32]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([NH:25][C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]4[N:12]([S:15]([C:18]5[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=5)(=[O:16])=[O:17])[CH:13]=[CH:14][C:3]=34)[CH2:27]2)=[O:43])[CH:40]=[C:39]([Cl:41])[CH:38]=1
Reactant: N[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1N[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
To a solution of methyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.35 g, 3.70 mmol, 1.0 eq), (R)-1-(3-aminopiperidin-1-yl)-2-((3,5-dichlorophenyl)amino)ethanone (1.34 g, 4.44 mmol, 1.2 eq) in PhCH3 (10 mL) was added Pd(OAc)2 (83 mg, 0.370 mmol, 0.1 eq), xantphos (250 mg, 0.43 mmol, 0.15 eq) and Cs2CO3 (2.82 g, 8.64 mmol, 3.0 eq) and the mixture was heated at 100° C. for 16 h. The reaction was cooled to rt, filtered through Celite, and concentrated in vacuo to afford a residue which was purified by silica gel column chromatography (PE/EA=10:1) to give brown solid (451 mg, yield: 21%). 1H NMR (400 MHz, CDCl3) δ: 8.90 (d, 1H), 8.74˜8.73 (m, 1H), 8.01˜7.94 (m, 2H), 7.54˜7.48 (m, 1H), 7.21˜7.19 (m, 2H), 6.75 (d, 1H), 6.69˜6.68 (m, 1H), 6.42˜6.32 (m, 2H), 5.11˜5.10 (m, 1H), 4.42˜4.38 (m, 1H), 3.92˜3.75 (m, 5H), 3.56˜3.52 (m, 2H), 3.23˜3.20 (m, 1H), 3.09˜3.03 (m, 1H), 2.30 (m, 3H), 2.14˜2.10 (m, 1H), 1.86˜1.72 (m, 1H), 1.69˜1.57 (m, 2H). ESI-MS: 630.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:26]=[CH:25][C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:4](=[O:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>CN(C=O)C>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:26]=[CH:25][C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:4](=[O:27])[CH:3]=1
Reactant: O=C(N1CCc2ccc(CCn3ccc(O)cc3=O)cc2CC1)C(F)(F)F
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 200 mg (0.53 mmol) 4-hydroxy-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (preparation 21b) in DMF is added 145 mg (1.05 mmol) potassium carbonate and the mixture is stirred 10 min at RT before 133 mg (0.53 mmol) 2-(bromomethyl)-pyridine hydro-bromide is added. The reaction mixture is stirred 5 h at RT and is directly purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 5:95).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O.[CH3:18][N:19]([CH3:23])[C:20]([NH2:22])=[S:21].O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CCO.CC(C)=O>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH3:18][N:19]([CH3:23])[C:20]1[S:21][CH:3]=[C:4]([C:6]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:22]=1
Reactant: CN(C)C(N)=S
Reactant: O=C(CBr)C1(c2ccccc2)CCNCC1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: CN(C)c1nc(C2(c3ccccc3)CCNCC2)cs1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of 7.26 g of the compound obtained in step B) and 2.08 g of the compound obtained in step A) in 150 ml of EtOH is refluxed for 1 hour 30 minutes. After cooling to RT, the mixture is concentrated under vacuum, the residue is taken up with water, rendered alkaline to pH 10 by the addition of 10% NaOH solution and extracted with DCM, the organic phase is washed with 10% NaOH solution and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained is dissolved in acetone, a solution of 3.31 g of p-toluenesulfonic acid monohydrate in 10 ml of acetone is added dropwise and the crystalline product formed is wrung to give 6.1 g of the expected product. M.p.=164° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:16]1[CH2:20][O:19]C(=O)[O:17]1)[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[NH:15])[NH:9]1.[OH-].[Ba+2].[OH-]>>[NH2:3][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[NH:15])[NH:9]1)[CH:16]([OH:17])[CH2:20][OH:19]
Reactant: N=C1CCCCC(CCCC(N)C2COC(=O)O2)N1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Product: N=C1CCCCC(CCCC(N)C(O)CO)N1

Procedure:
The product of EXAMPLE 272 is treated with aqueous barium hydroxide at 70° C., to yield the title material.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH:17]1([CH2:20][O:21][CH:22]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[C:23](N(OC)C)=[O:24])[CH2:19][CH2:18]1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:23](=[O:24])[CH:22]([O:21][CH2:20][CH:17]3[CH2:18][CH2:19]3)[C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:33][CH:34]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: CON(C)C(=O)C(OCC1CC1)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OCC3CC3)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(cyclopropylmethoxy)-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(cyclopropylmethoxy)-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc/hexanes) gave the product as a pale yellow solid (0.092 g, 23% yield). MS: m/z 556.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:39]1[N:40]=[C:41]([CH3:45])[N:42]([CH3:44])[CH:43]=1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[CH3:44][N:42]1[CH:43]=[C:39]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:10]4[S:9][C:5]5[C:6](=[O:8])[NH:7][C:2]([CH3:31])([CH3:1])[CH2:3][C:4]=5[N:11]=4)[C:17]=3[CH:18]=2)[N:40]=[C:41]1[CH3:45]
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(B5OC(C)(C)C(C)(C)O5)cc43)sc2C(=O)N1
Reactant: Cc1nc(Br)cn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1C
Temperature: 140 °C
Yield: 14.4 %

Procedure:
To a solution of Example 292 (75 mg, 0.17 mmol) in THF (3 mL) and water (1 mL) was added tetra-n-butylammonium bromide (107 mg, 0.34 mmol), sodium carbonate (36 mg, 0.34 mmol), 4-bromo-1,2-dimethyl-1H-imidazole (60 mg, 0.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The reaction was heated at 140° C. under microwave irradiation for 25 minutes. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL); the organic fraction was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to yield the title compound (10 mg, 14%) as an off-white solid. δH (CDCl3) 8.09 (1H, d, J 2.1 Hz), 7.48 (1H, dd, J 8.5 and 2.1 Hz), 7.02 (1H, s), 6.95 (1H, d, J 8.5 Hz), 5.22 (1H, br. s), 4.36-4.29 (2H, m), 4.24-4.19 (2H, m), 3.60 (3H, s), 2.88 (2H, s), 2.42 (3H, s), 1.40 (6H, s). LCMS (ES+) 410.0 (M+H)+, RT 1.86 minutes (Method 1).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC(=O)C=Cc1cc(Cl)ccc1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(Cl)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (9.5 g) was added at room temperature diethyl malonate (4.5 g) and then added little by little 4-(5-chloro-2-methylphenyl)-3-buten-2-one (5.5 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (15 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (15 ml) for 15 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-chloro-2-methylphenyl)cyclohexane-1,3-dione (2.9 g) as colorless crystals.
Reaction SMILES: [AlH4-].[Li+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([NH2:23])=O)[CH2:17][CH2:16]1)[CH3:14]>O1CCCC1>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][NH2:23])[CH2:19][CH2:20]1)[CH3:14]
Reactant: CC(C1COc2ccccc2O1)N1CCC(C(N)=O)CC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C1COc2ccccc2O1)N1CCC(CN)CC1

Procedure:
In a suspension of 30 g lithium aluminohydride in 1000 ml tetrahydrofuran 78 g of the carboxamide of step F as the solid is added thereto portionwise.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=O>[OH-].[Na+].O.C(O)(C)C.[Ni].[Mo]>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: [Mo]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
When using the procedure of Example 5, 48.7 grams (0.18 mole) of 2-nitro-2'-hydroxy-5'-methylazobenzene (95% pure) was dissolved in a solution of 9 grams of sodium hydroxide in 30 grams of water and 45 grams of isopropanol, and a total of 7.0 grams of a 50% slurry in water of molybdenum-promoted Raney nickel catalyst (W. R. Grace Raney No. 30) were added in two equal 3.5 grams portions at the start and at the half way point of the hydrogenation, the product, 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole was obtained in very high yield after removal of the suspended nickel catalyst by filtration and acidification of the filtrate to a pH value of less than 4 using aqueous sulfuric acid.
Reaction SMILES: C([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10]O)(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.C(O)(C(F)(F)F)=O.[CH3:53][C:54]1[CH:55]=[CH:56][C:57]([S:60]([OH:63])(=[O:62])=[O:61])=[CH:58][CH:59]=1>>[C:54]1([CH3:53])[CH:55]=[CH:56][C:57]([S:60]([OH:63])(=[O:61])=[O:62])=[CH:58][CH:59]=1.[NH2:8][C@H:9]1[CH2:10][O:14][C:12]1=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COC1=O

Procedure:
Boc serine is treated with Ph3P, DEAD, and TFA , followed by TsOH to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:32]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[N:31]=[CH:30][CH:29]=1)CCC>>[CH3:11][C:9]1[N:10]=[C:5]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:3]([CH3:22])[C:2]([C:28]3[N:32]([C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[N:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: Cc1cn2cc(Br)c(C)c(-c3cccc(C(F)(F)F)c3)c2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: Cc1cn2cc(-c3ccnn3-c3ccc(C#N)cc3)c(C)c(-c3cccc(C(F)(F)F)c3)c2n1

Procedure:
The title compound was prepared from 6-bromo-2,7-dimethyl-8-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (Int. 8, 50 mg, 0.136 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 125 mg, 0.270 mmol) using a similar method to that used in Example 1 (Step 4) (61 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>O1CCCC1>[Cl:14][CH2:15][CH2:16][C:17]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:18]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Product: O=C(CCCl)N(c1ccccc1)c1ccccc1
Yield: 48.1 %

Procedure:
To a solution of 40.6 g (0.240 mole) of diphenylamine in 150 ml of tetrahydrofuran (THF) was added dropwise a solution of 20.0 g (0.160 mole) of 3-chloropropionyl chloride in 100 ml of THF. The reaction mixture was stirred mechanically and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate was concentrated under reduced pressure. The residue was partitioned between methylene chloride and water (200 ml each). The methylene chloride layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give an amorphous solid. The solid was recrystallized from THF to yield 20.0 g (48%) of the title compound as a white, crystalline solid, mp 93°-94° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[O:32])=[CH:29][CH:28]=1>O1CCCC1>[F:39][C:35]1[CH:34]=[C:33]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])=[CH:41][CH:40]=2)=[O:32])[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccc(F)c1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes, then cooled to room temperature. 4-Amino-3'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion and the reaction mixture heated at reflux for 48 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue dissolved in ethyl ether and filtered. The filtrate was washed with 3N HCl (50 mL) and water. The ether extract was dried (MgSO4) and concentrated in vacuo to an off-white solid. Purification by flash column chromatography (5% v/v ethyl ether/methylene chloride) yielded the title propanamide as a tan solid (1.13 g, 55%); mp 169°-171° C. 1H-NMR (300 MHz, d6 -DMSO): 7.50-7.64 (m, 4H, aromatic) 7.77-7.82 (m, 2H, aromatic) 7.94-7.98 (m, 2H, aromatic) 9.84 (s, 1H, NH) 10.85 (bs, 1H, OH). MS (CI, CH4): 410 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>>[F:8][C:9]1[CH:10]=[C:11]([O:15][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:12]=[CH:13][CH:14]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)CCCCl
Product: O=C(CCCCl)Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Chlorobutyrylchloride (35.3 g) was added to 3-fluorophenol (25 g). This mixture was stirred during 48 h at room temperature. After the reaction was completed the product was purified by vacuo-destillation. Yield: 35,3 g (b.p. 106° C. 3 mmHg) of 4-chloro-butanoic acid 3-fluorophenyl ester as a white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1Cl
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).