Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C@H:6]1[CH2:21][N+:22]([O-])=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.C1(C)C=CC=CC=1>C1COCC1>[NH2:22][CH2:21][C@H:6]1[C@H:5]([CH2:3][OH:2])[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: COC(=O)[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1CO

Procedure:
A solution of trans-8-Chloro-11-nitromethyl-10,11-dihydro-dibenzo[b,f]oxepine-10-carboxylic acid methyl ester (8) (5.0 g, 13.23 mmol) in dry THF (25 ml) is added at −15° C. to a mixture of THF (25 ml) and 3.5 M LAH suspension in THF/Toluene (16.4 ml, 57.5 mmol).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]2[N:9]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][C:15]5[C:16]4=[C:11]([CH:12]=[CH:13][CH:14]=5)[C:10]3=[N:23][C:5]=2[CH:4]=1.[C:26]1([CH3:37])[CH:31]=[CH:30][C:29]([S:32]([O:35]C)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCOCC>[CH3:37][C:26]1[CH:27]=[CH:28][C:29]([S:32]([O-:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1.[CH3:26][N:23]1[C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[CH:22]=[CH:21][CH:20]=[C:17]([C:18](=[O:19])[N+:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:4][C:5]1=2)[C:16]=34
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: O=c1c2cccc3cccc(c32)c2nc3cc(C(F)(F)F)ccc3n12
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cn1c2[n+](c3ccc(C(F)(F)F)cc31)C(=O)c1cccc3cccc-2c13
Yield: 50.5 %

Procedure:
Six grams (0.018 m.) of 11-(trifluoromethyl)-7H-benzimidazo[2,1-a]benz[de]isoquinoline-7-one were heated to about 100° C. in 25 ml. of methyl p-toluenesulfonate for about 16 hours under a nitrogen atmosphere. After cooling, the solution was poured into ether. The solids were collected and recrystallized twice from methanol/ether to give 4.7 g. (50.5 percent yield) of the desired product, m.p. about 263°-265° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:6]=1)=[O:4].O.O[Li].O.Cl>C1COCC1>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[N:6]=[C:5]2[C:3]([OH:4])=[O:2])([O-:16])=[O:15]
Reactant: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-nitro-1-trityl-1H-indazole-3-carboxylic acid methyl ester 19AP (12.95 g, 27.96 mmol) in THF (270 ml) and H2O (135 ml) was added LiOH.H2O (2.34 g, 55.92 mmol) at room temperature. After stirring for overnight at room temperature, it was cooled to 0° C. and acidified with slow addition of 1N HCl (55.9 ml, 55.92 mmol). Reaction mixture was concentrated under reduced pressure. Solid was collected by filtration and washed with water to give desired 5-nitro-1-trityl-1H-indazole-3-carboxylic acid 20AP (12.06 g, 96%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Cl:1][C:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2cccnc2n1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A solution of N-chlorosuccinimide (24 mg, 0.18 mmol) in DMF (0.1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl}carbamate (60 mg, 0.17 mmol) (5073-171) in N,N-dimethylformamide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The mix was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc/hexane) to give the desired product (26 mg, 40%). LCMS calculated for C20H22ClFN3O2(M+H)+: m/z=390.1. Found: 390.1.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16]([Cl:19])(=[O:18])=[O:17])[C:7]=1[OH:20])(=O)C.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[ClH:19].[NH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[C:8]([S:16](=[O:17])(=[O:18])[N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[C:7]=1[OH:20]
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Reactant: CCNCC
Product: CCN(CC)S(=O)(=O)c1cc(C(C)(C)C)cc(CN)c1O
Product: Cl

Procedure:
This compound is prepared analagously to Examples 11 c and 11 d from 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol and diethylamine.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Cl.ClC[C:46]1[N:50](C)[N:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:50]([CH3:46])[N:49]=[CH:48][N:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncnc1CCl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cl
Product: Cn1ncnc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride and isolated as colorless gum. MS (m/e): 378.3 (MH+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(N[S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])C=CC=CC=1.[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([OH:40])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]>CO>[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([O:40][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(O)cc1O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 40 h
Yield: 36 %

Procedure:
To a solution in 2-[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 18, (0.312 g, 1.23 mmol) in MeOH (10 mL) containing diisopropylethylamine (0.214 mL, 1.23 mmol) at 0° C. under N2 is added N-phenyltrifluoromethanesulfonamide (0.439 g, 1.23 mmol). The reaction is warmed slowly to room temperature and stirred for 40 hours. The solvent is removed under reduced pressure and the crude oil which remains is purified over silica (EtOAc:heptane 1:9) to afford 0.170 g (36% yield) of the desired compound as a yellow oil. 1H NMR (250 MHz, MeOD) δ ppm 8.85 (1 H, br s), 8.19 (1 H, d, J=2.4 Hz), 7.46 (1H, d, J=2.3 Hz), 3.74 (3 H, s), 1.63 (6 H, s). HPLC-MS: m/z 387 [M+H]+.
Reaction SMILES: [CH3:1][C:2](C)([CH2:7][C:8]1C=C[CH:11]=[C:10](O)[CH:9]=1)[C:3]([O:5]C)=[O:4].[C:16]1([CH:22]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23][N:24]([CH2:37][CH2:38][CH2:39][OH:40])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=2[Cl:36])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(O[CH:77]([CH3:79])[CH3:78])=O)=O)C>C1COCC1.O>[C:41]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[C:27]=2[Cl:36])[CH2:37][CH2:38][CH2:39][O:40][C:11]2[C:77]([CH3:78])([CH3:79])[CH:7]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:8]=[CH:9][CH:10]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: COC(=O)C(C)(C)Cc1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
A solution of methyl 2,2-dimethyl-3-(3-hydroxyphenyl)propionate (135 mg, 0.65 mmol) and N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-hydroxypropylamine (290 mg, 0.65 mmol) in THF (8 mL) was treated with Ph3P (170 mg, 0.65 mmol), diisopropylazodicarboxylate (135 mg, 0.65 mmol), and stirred for 16 h. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried, and concentrated. Purification via silica gel column chromatography eluted with 30% EtOAc:hexane yielded the titled compound (200 mg, 50%). MS (ESI) 639 (M+H+).
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]1[CH2:13][CH:14]=[CH2:15].[Br:16]N1C(=O)CCC1=O>O>[Br:16][CH2:15][CH:14]1[CH2:13][N:3]2[C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:1]1
Reactant: C=CCn1c(=O)[nH]c2ccccc2c1=N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Product: O=C1Nc2ccccc2C2=NC(CBr)CN12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a suspension of 3,4-dihydro-4-imino-3-allyl-2(1H)-quinazolinone (0.5 g, 2.5 mmol) in water (30 mL) was added N-bromosuccinimide (443 mg, 2.5 mmol). The mixture was allowed to stir at room temperature for 30 minutes. The solid was collected by filtration and washed with water (10 mL) to afford 2-bromomethyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one (680 mg, 97%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=O.N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[C:14]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([C:2]#[N:1])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc(C(N)=O)cc(C(C)(C)C)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#N)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of give methyl 3-(aminocarbonyl)-5-tert-butylbenzoate (11.8 g, 0.0451 mol) in THF (88) was added pyridine (5.5 mL, 0.068 mol) and TFAA (9.6 mL, 0.068 mol). The reaction mixture was allowed to stir at rt for 3 h and then quenched by the addition of aq sat NaHCO3 and brine. The mixture was extracted with EtOAc. The organic solutions were combined and washed with sodium bicarbonate, brine, 1M HCl, water and brine. The solution was dried over MgSO4, filtered, and concentrated to give methyl 3tert-butyl-5-cyanobenzoate (9.5 g, 70% pure, 68%). 1H NMR (400 MHz, d6-DMSO) δ: 8.77 (s, 1H), 8.48 (s, 1H), 8.19 (m, 1H), 8.17 (m, 1H), 8.15 (1, m), 3.88 (s, 3H), and 1.31 (s, 9H). LCMS: ES+ 218.2
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1
Reactant: [H][H]
Reactant: CCOC(=O)CC1(C)C=Cc2c(C)cc(C)c(C)c2O1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1(C)CCc2c(C)cc(C)c(C)c2O1
Yield: 92.9 %

Procedure:
A solution of ethyl (2,5,7,8-tetramethyl-2H-chromen-2-yl)acetate (20.00 g) in methanol (MeOH) (300 ml) was hydrogenated in the presence of 10% palladium on carbon (50% wet, 4.0 g) in one atmosphere of hydrogen at room temperature for 16 hours. The catalyst was filtered off and MeOH was removed under reduced pressure to give a residue. The residue was purified by chromatography over silica gel (AcOEt-hexane 3:97 as eluent) to give ethyl (2,5,7,8-tetramethylchroman-2-yl)acetate as an oil (18.72 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[CH:4][CH:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](B(O)O)[CH:26]=2)[CH:21]=[CH:20]1>>[ClH:1].[ClH:1].[ClH:1].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:2]3[N:7]=[CH:6][C:5]([O:8][C@@H:9]4[CH:16]5[CH2:17][N:12]6[CH2:13][CH:14]([CH2:18][CH:10]4[CH2:11]6)[CH2:15]5)=[CH:4][CH:3]=3)[CH:26]=2)[CH:21]=[CH:20]1
Reactant: Clc1ccc(OC2C3CC4CC2CN(C4)C3)cn1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Product: Cl
Product: c1cc2ccc(-c3ccc(OC4C5CC6CC4CN(C6)C5)cn3)cc2[nH]1

Procedure:
Prepared from the product of Example 15B (115 mg, 0.434 mmol) and 1H-indol-6-ylboronic acid using the microwave Suzuki coupling Method G and the salt formation Method H to provide the titled compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.93-2.05 (m, 2H), 2.24 (s, 1H), 2.40 (s, 1H), 2.44 (s, 1H), 2.59 (s, 2H), 3.61 (s, 2H), 3.67-3.81 (m, 4H), 5.19 (t, J=3.2 Hz, 1H), 6.61 (d, J=3.1 Hz, 1H), 7.48-7.55 (m, 2H), 7.82 (d, J=8.5 Hz, 1H), 7.97 (s, 1H), 8.31-8.36 (m, 1H), 8.36-8.42 (m, 1H), 8.62 (d, J=2.4 Hz, 1H). MS (DCI/NH3) m/e=346 (M+H)+. Anal. calcd. for C22H23N3O.3HCl.0.3H2O: C, 57.42; H, 5.83; N, 9.13. Found C, 57.46; H, 5.98; N, 9.01.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][C:18]3[O:19][C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:21]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][C:18]3[O:19][C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[N:22]=3)=[CH:35][CH:36]=2)[N:10]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)oc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cc2nc(CCC(=O)O)c(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of methyl 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-5-phenyl-4-oxazolyl]propionate (489 mg), lithium hydroxide hydrate (127 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3.1 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-5-phenyl-4-oxazolyl]propionic acid (448 mg, yield 94%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 154–155° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH2:15][NH2:16])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:16][CH2:15][C:5]1([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NCC1(CC2CC2)CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(CC2CC2)CCC2(CC1)OCCO2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {[8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]dec-8-yl]methyl}amine (7 g; 31.0 mmol) and n-ethyldiisopropylamine (6.45 ml; 37.2 mmol) in DCM (60 ml) at 0° C. was added 2,4-dichlorobenzoyl chloride (4.781 ml; 34.17 mmol) dropwise and the solution stirred for 4 hours warming to ambient temperature. The reaction was partitioned between DCM (50 ml) and water (20 ml). The aqueous phase was extracted with DCM (20 ml) and the combined organics dried over MgSO4, filtered and evaporated to give a colourless oil which was used in the next step without further purification. (11.5 g) 1H NMR δ (ppm) (CDCl3): 7.67 (1H, d, J=8.3 Hz), 7.43 (1H, d, J=2.0 Hz), 7.32 (1H, dd, J=2.0, 8.4 Hz), 6.25 (1H, s), 3.93 (4H, s), 3.56 (2H, d, J=6.2 Hz), 1.67 (8H, m), 1.33 (2H, d, J=6.7 Hz), 0.75-0.65 (1H, m), 0.51-0.47 (2H, m), 0.05 (2H, q, J=5.0 Hz). MS (m/e)=398
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12](O)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24](=O)([O-])[O-:25].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([CH2:24][O:25][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(COc2ccccc2)cc(C(=O)OC)c1

Procedure:
A mixture of 5-hydroxyisophthalic acid dimethyl ester (700 mg; 3.33 mmol), benzyl bromide (635 mg; 3.70 mmol), and potassium carbonate (510 mg; 3.7 mmol) in acetone was refluxed overnight. After cooling, the mixture was partitioned between water and ethyl acetate. The layers were separated, the aqueous layer was extracted twice more with ethyl acetate, and the combined organic portions were washed with brine, dried, and concentrated to provide a crude solid. Recrystallization from ethyl acetate/hexanes furnished the product as a white crystalline material, mp 95-97° C., 1H NMR (400 MHz): d 3.94 (s, 6H); 5.15 (s, 2H): 7.42 (m, 5H); 7.84 (s, 2H); 8.29 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]2SCCCS2)=[CH:5][C:4]=1[CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([SnH](CCCC)CCCC)CCC.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH3:11])=[CH:5][C:4]=1[CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCCCC(CC(=O)OC)c1cc(C2SCCCS2)c(OC)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCC(CC(=O)OC)c1cc(C)c(OC)cc1OC
Temperature: 100 °C
Yield: 92.5 %

Procedure:
A solution of 558 mg (1.35 mmol) of methyl 3-[2,4-dimethoxy-5-(1,3-dithian-2-yl)phenyl]octanoate [prepared as described in step (i) above], 1.576 g (5.42 mmol) of tributyltin hydride and 15 mg of azobis(isobutyronitrile) in 20 ml of toluene was stirred whilst heating at 100° C. for 6.5 hours. At the end of this time, the reaction temperature was allowed to reduce to room temperature, and the reaction mixture was purified by column chromatography through 15 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 6:0 to 6:1 by volume as the eluent, to give a mixture containing the reduced product. The mixture was further purified by column chromatography through 30 g of alumina, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 20:0 to 20:1 by volume as the eluent, to give 385 mg (yield 92%) of methyl 3-(2,4-dimethoxy-5-methylphenyl)octanoate as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](CS(C)(=O)=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(N1CCN(C2C=CC=C(CCl)C=2)CC1)=O)(C)(C)C.[CH3:46][S:47]([O-:49])=[O:48].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:47]([CH3:46])(=[O:49])=[O:48])[C:15]=2[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CS(C)(=O)=O)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CCl)c2)CC1
Agent: [Na+]
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)cccc1S(C)(=O)=O

Procedure:
4-(3-Methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tert-butyl ester may be prepared in the following manner: on carrying out the operation according to the procedure of Example 10 starting with 1.55 g of 4-(3-chloromethylphenyl)piperazine-1-carboxylic acid tert-butyl ester and 0.766 g of sodium methanesulfinate, 0.9 g of 4-(3-methanesulfonyl-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester is obtained in the form of a beige powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1.C(N(CC)CC)C.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]1([CH:12]2[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:8][CH:7]2[O:6][CH2:5][C:4]2[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=2[CH2:2][NH:1][C:37]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:44])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(OCc2ccccc2CN)C1
Reactant: O=C(O)c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(OCc2ccccc2CNC(=O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.5 %

Procedure:
A solution of 150 mg (0.38 mmol) of tert-butyl (3RS,4RS)-3-(2-aminomethyl-benzyloxy)-4-phenyl-piperidine-1-carboxylate in 2 ml of methylene chloride was treated with 229 mg (2.26 mmol) of triethylamine, 139 mg (1.05 mmol) of nicotinic acid, 216 mg (1.13 mmol) of EDC and 10 mg (0.08 mmol) of 4-dimethylaminopyridine and the mixture was stirred at room temperature for 24 hours. Thereafter, the reaction solution was diluted with methylene chloride and washed with a saturated sodium hydrogen carbonate solution. The organic phase was separated, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate as the eluent. There were obtained 100 mg (53% of theory) of tert-butyl (3RS,4RS)-4-phenyl-3-(2-{[(pyridine-3-carbonyl)-amino]-methyl}-benzyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 502 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH2:27])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3ccc(F)cc3)cc2F)cn1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 4-fluorophenethylamine (0.234 g, 1.68 mmol) and 3 Å molecular-sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.383 g, 65%): TOF MS ES+ 385.1 (M+H)+, HRMS calcd for C20H19N4O2F2 385.1476 (M+H)+, found 385.1480, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=11.1 min, 100% purity.