Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:36]=[C:35]([CH3:37])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:27])=[O:26])[CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:36]=[C:35]([CH3:37])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:26])=[O:27])[CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(S(=O)(=O)N5CCN(C)CC5)c4)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3cccc(S(=O)(=O)N4CCN(C)CC4)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine (0.0742 mmol, 1.0 equiv) was dissolved in 5 ml, anhydrous DCM and placed under an argon atmosphere. 200 mL of BBr3 (0.1 M) was added via syringe to the amine solution and stirred at room temperature for 2 h. BBr3 was quenched with saturated NaHCO3 until pH was adjusted to 7. The mixture was filtered and rinsed with water and Et2O to give 4-chloro-3-{5-methyl-3-[3-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol, as a tan solid (24.3 mg, 62% yield). 1H NMR (DMSO-d6): δ 2.71 (s, 6H), 2.72 (bs, 2H), 3.16 (m, 2H), 3.46 (m, 2H), 3.78 (m, 2H), 6.88 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.95 (d, J=2.9 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.45 (dd, J=7.9 Hz, J=1.7 Hz, 1H), 7.72 (t, J=8.1 Hz, 2H), 7.91 (d, J=1.7 Hz, 1H), 8.12 (dd, J=8.3 Hz, J=1.7 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.93 (d, J=1.9 Hz, 1H), 9.99 (s, 1H), 11.46 (s, 1H). MS (ES+): m/z=526. Elemental for C25H36Cl2N6O8S 5H2O Calculated: C, 46.08; H, 5.57; N, 12.90. Found: C, 46.84; H, 5.04; N, 12.66.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:8]=[C:7]([C:22]#[N:23])[C:6]=1[C:24]#[C:25][Si](C)(C)C)(=[O:3])[CH3:2].C(=O)([O-])[O-].O.CCOCC>CO>[C:1]([NH:4][C:5]1[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:12][C:11]=2[Cl:21])[N:8]=[C:7]([C:22]#[N:23])[C:6]=1[C:24]#[CH:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C#C[Si](C)(C)C)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1NC(C)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-acetamido-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trimethylsilylethynylpyrazole (20 mg, the compound of Example B2) in methanol (1 ml) was added potassiun carbonate (20 mg). The reaction mixture was stirred at room temperature for 40 minutes and then poured into water (20 ml) and ether (20 ml). The organic layer was separated, dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel eluted with ether to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Reactant: Oc1ccc(Cl)cc1
Product: Cc1cc(Nc2cc3c(C)cccc3c(Oc3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenoxy)-5-methyl-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 366(MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]([CH2:25][CH2:26][OH:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]([CH2:25][CH:26]=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N(CCO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N(CC=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
To a solution of oxalyl chloride (13.8 ml) in dichloromethane (270 ml) was added dropwise a solution of dimethyl sulfoxide (19.7 ml) in dichloromethane (30 ml) below -60° C. under atmosphere of nitrogen. After stirring the mixture at the same condition for 30 minutes, a solution of 2-(N-allyloxycarbonyl-N-benzylamino)ethanol (32.6 g) in dichloromethane (30 ml) was added to the mixture below -60° C. with stirring. After 30 minutes, triethylamine (58 ml) was added to the mixture at the same condition. The mixture was stirred below -60° C. for 30 minutes and the reaction temperature was allowed to rise to ambient temperature. The mixture was washed with water (300 ml), 1N hydrochloric acid (300 ml×2), saturated aqueous sodium hydrogen carbonate (300 ml), and brine (300 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-(N-allyloxycarbonyl-N-benzylamino)acetaldehyde (32.9 g) as a syrup.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CCc1ccccc1
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
To a stirring mixture of trans-β-nitrostyrene (5.25 g, 0.035 mol) and silica gel (10 g, 230-400 mesh) in chloroform (400 mL) and isopropanol (75 mL) at room temperature, was slowly added sodium borohydride (5.50 g, 0.145 mol) over a period of 45 min. The reaction mixture was stirred for an additional 15 min and then carefully quenched with 10% hydrochloric acid (20 mL). Separated solid was filtered and washed with chloroform (50 mL). Combined filtrate and washing was washed with water (1×20 mL), brine (1×20 mL) and dried over anhydrous sodium sulfate. Solvent evaporation at reduced pressure gave a crude material which was purified by flash chromatography (silica gel, 8% ethyl acetate-hexane) to give 2.86 g of 1-nitro-2-phenylethane as a colorless oil (spicy odor); Rf (10% ethyl acetate in hexane) : 0.40; 1H-NMR (300 MHz, CDCl3) 7.40-7.20 (m, 5H), 4.60 (t, 2H), 3.30 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]([F:13])([F:12])[F:14])=[CH:4][N:3]=1
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)cnc1N

Procedure:
0.44 g of 2-amino-3-nitro-5-trifluoromethylpyridine (starting material B2) dissolved in 50 ml methanol are hydrogenated over 0.05 g of 10% strength Pd/C until no starting material is detectable by TLC. After filtration, the solvent is evaporated and the solid residue is dried in vacuo. This gives 0.366 g of the title compound of m.p. 97–99° C. The mass spectrum shows the molecular peak MH+ at 178.3 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Clc1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Next, a mixed solution of 22 g of 2-(4-chlorophenyl)nitrobenzene, 61 g of triphenylphosphine and 190 ml of o-dichlorobenzene was refluxed for 6 hours under a nitrogen flow. The solution was cooled to room temperature, o-dichlorobenzene was then distilled away under reduced pressure, and the concentrate was purified by silica gel column chromatography, and vacuum-dried to obtain 17.7 g of 2-chloro-9H-carbazole.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[Ce+3].[Cl-].[Cl-].[B-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1C=C(c2cccnc2F)CC1
Agent: [B-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: OC1C=C(c2cccnc2F)CC1
Reaction time: 0.5 h

Procedure:
A solution of 3-(2-fluoropyridin-3-yl)cyclopent-2-enone (1582 mg, 8.93 mmol) in Tetrahydrofuran (20 mL) and Methanol (20 mL) was cooled to 0° C. under nitrogen. Cerium (III) chloride (2201 mg, 8.93 mmol) was added, followed by sodium borohydrate (676 mg, 17.86 mmol) in 4 lots, over 15 min. After 30 min, the reaction was quenched with saturated ammonium chloride solution (20 mL—effervescence!), and partitioned between dichloromethane (100 mL) and saturated ammonium chloride solution (30 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, dried over MgSO4, and concentrated, affording the product as a yellow oil. MS (ESI, pos. ion) m/z: 180.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:44])[O:26][CH:27]([O:29][C:30](=[O:43])[CH2:31][CH2:32][C:33]([O:35]CC2C=CC=CC=2)=[O:34])[CH3:28])[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].ClC1C=C(NC2C=CC=CC=2NC(=O)OCOC(=O)CCC(OCC2C=CC=CC=2)=O)C=CC=1C(=O)C1C=CC=CC=1C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:44])[O:26][CH:27]([O:29][C:30](=[O:43])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH3:28])[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OC(C)OC(=O)CCC(=O)OCc2ccccc2)cc1Cl
Agent: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OCOC(=O)CCC(=O)OCc2ccccc2)cc1Cl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OC(C)OC(=O)CCC(=O)O)cc1Cl

Procedure:
By following the procedure of example 23, but substituting 1-(3-(benzyloxycarbonyl)-propanoyloxy)ethyl N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]carbamate (Compound 206) for 1-(3-(Benzyloxycarbonyl)propanoyloxy)methyl N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]carbamate (Compound 204), the desired compound was obtained. Purification was done by chrormatography using Et2O/hexane 4:1 as eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>>[OH:29][C@:25]([C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1

Procedure:
10-Bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (50 mg) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 5.7 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 379 (M)+. 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 7.33 (dd, J=8.5, 2.2 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.50 (d, J=18.3 Hz, 1H), 6.35 (s, 1H), 4.49 (s, 4H), 2.39 (d, J=11.3 Hz, 3H), 1.80 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:4][OH:5].[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1.O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[CH2:3][CH:4]=[O:5]
Reactant: CC(CCO)CCC1CCCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC=O)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
To a cooled (0° C.) mixture of 3-methyl-5-cyclohexylpentanol (50 g, 0.27 mol), water (50 ml), potassium bromide (3.2 g), and 1 mol % TEMPO (0.4 g) in 150 ml of toluene was added aqueous sodium hypochlorite (12% available chlorine, 167 g), buffered to pH=9.6 with 2.4 g of sodium bicarbonate over a period of 30 minutes. The reaction mixture was warmed to room temperature and stirred for 15 minutes. The organic layer was separated and washed sequentially with 250 ml KI solution (4.4 g of KI, 18 ml of 36% HCl, diluted to 250 ml), 50 ml of 5% sodium thiosulfate, and 50 ml of saturated aqueous sodium chloride. The organic phase was dried with magnesium sulfate and roto-evaporated to remove the toluene. The residue was distilled at 80° C. and 0.5 mmHg to yield the product (40 g, 80% yield) as a clear liquid. MS (EI) m/z (relative intensity) 182 (M+).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH3:16])=[CH:8][C:7]=1[OH:17])[CH:2]=[CH2:3].Br[CH2:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][CH2:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:7]([O:17][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:40][CH:41]=2)=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH3:16])=[CH:10][C:11]=1[CH3:12])[CH:2]=[CH2:3]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)cc1
Reactant: C=CCOC(=O)c1c(C)cc(OCCC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)cc(OCCC)cc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
A mixture of the title C compound, 2-hydroxy-6-methyl-4-propoxy-benzoic acid allyl ester (400 mg, 1.6 mmol), the title C compound in Example 11, 4-[2-(4-bromomethyl-phenoxy)-ethyl]-5-methyl-2-phenyl-oxazole (595 mg, 1.6 mmol) and potassium carbonate (662 mg, 4.79 mmol) in 15 mL of DMF is stirred at RT overnight. The mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue is chromatographed on silica gel using 15% EtOAc in hexane as the eluent to obtain 2-methyl-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}4-propoxy-benzoic acid allyl ester as an oil: ESI-MS 542 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br[CH2:15][C:16]([C:18]1[CH:22]=[C:21]([Cl:23])[S:20][C:19]=1[Cl:24])=O>>[Cl:24][C:19]1[S:20][C:21]([Cl:23])=[CH:22][C:18]=1[C:16]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:15]=1
Reactant: O=C(CBr)c1cc(Cl)sc1Cl
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3cc(Cl)sc3Cl)cs2)cc1
Yield: 74 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dichlorothiophene to obtain methyl 4-[4-(2,5-dichloro-3-thienyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 74%. Pale yellow prisms. Melting point: 149 to 150° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OCCF)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
A stirred solution of 7.0 grams (0.035 mole) of methyl 4-(2-fluoroethoxy)benzoate and 75 ml of a 1.0 M solution of diisobutylaluminium hydride in hexanes in 75 ml of toluene was heated at 40° C. for three hours. The mixture was cooled and quenched with methanol. This mixture was stirred at room temperature for approximately 18 hours and was filtered through a pad of celite. The filter cake was washed with a small amount of methanol. The combined filtrate was evaporated under reduced pressure to yield 5.0 grams of 2-fluoroethyl 4-hydroxymethylphenyl ether as an oil which slowly solidified.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:20]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[CH2:21][CH3:22].[H-].[Na+].[OH-].[Na+].Cl>CN(C)C=O.O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:20][CH2:21][CH3:22])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCCc1ncc[nH]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.5 %

Procedure:
Methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (1.50 g) and 2-propylimidazole (0.66 g) were dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (60% dispersion in oil, 0.30 g) was gradually added to the resulting solution at room temperature. After this was stirred at room temperature for 3.5 hours, an aqueous solution of 2 N sodium hydroxide (50 ml) was added thereto and stirred for an additional 30 minutes. Water was added to the reaction mixture, and the pH was then adjusted to 6 with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration, and recrystallized from ethanol to obtain 4-(4-chlorophenyl)-2-(2-propyl-1-imidazolyl)-5-oxazolepropionic acid (1.25 g, 69%) as pale brown needles. mp 174-175° C.
Reaction SMILES: [O:1]=[C:2]1[CH:19]=[CH:18][O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:4]2([O:17][CH:18]=[CH:19][C:2](=[O:1])[CH2:3]2)[CH2:5][CH2:6][NH:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C=CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=COC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 239.9 %

Procedure:
To a solution of tert-butyl 8-oxo-11-oxa-3-azaspiro[5.5]undec-9-ene-3-carboxylate (200 mg, 0.748 mmol) in CH2Cl2 (2.4 mL) was added TFA (0.6 mL, 7.8 mmol). The mixture was stirred at room temperature for 15 min. Solvent was removed. The crude material was evaporated again from toluene (2×) and dried under high vacuum overnight to provide 11-oxa-3-azaspiro[5.5]undec-9-en-8-one (300 mg). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.1 Hz, 1H), 5.57 (d, J=6.1 Hz, 1H), 3.45 (d, J=11.7 Hz, 2H), 3.34 (dd, J=24.1, 12.7 Hz, 2H), 2.67 (s, 2H), 2.38 (d, J=14.6 Hz, 2H), 1.98 (td, J=14.8, 4.8 Hz, 2H). ESI-MS m/z calc. 167.09, found 168.2 (M+1)+; Retention time: 0.17 minutes (3 minute run).
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:16]2[CH2:15][CH:14]3[N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:10]([CH2:11][N:12]([C:28](=[O:30])[CH3:29])[CH2:13]3)[C:9]=2[CH:8]=[N:7]1)(=O)C>C1COCC1.C(OCC)(=O)C.O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:17]2[CH:14]3[CH2:13][N:12]([C:28](=[O:30])[CH3:29])[CH2:11][CH:10]2[C:9]2[CH:8]=[N:7][NH:6][C:16]=2[CH2:15]3)(=[O:19])=[O:20])=[CH:26][CH:25]=1
Reactant: CC(=O)N1CC2Cc3c(cnn3C(C)=O)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Aqueous sodium hydroxide (3 N, 0.56 mL, 1.70 mmol) was added to a stirring solution of 1-[5-acetyl-12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-dien-10-yl]-ethanone (240 mg, 0.567 mmol) in THF (2 mL). The reaction mixture was stirred for 3 h at room temperature and subsequently diluted with ethyl acetate (10 mL) and water (5 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×5 mL). The organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 1-[12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-dien-10-yl]-ethanone as a white solid. Retention time (min)=1.242, method [1], MS (ESI) 381.0 (M+H); 1H NMR (300 MHz, CDCl3) (rotamers) δ 7.68-7.58 (m, 2H), 7.44 and 7.41 (2×s, 1H), 7.38-7.30 (m, 2H), 5.32-5.20 (m, 1H), 4.78 and 4.55 (2×d, J=13.2 Hz, 1H), 4.48-4.35 (m, 1H), 3.90-3.54 (m, 2H), 3.08-2.62 (m, 3H), 2.00 and 1.61 (2×s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29](Br)=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:13]2[CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=[CH:11][C:12]2=[O:15])=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1ccc(OCc2ccccc2)c[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2cc(OCc3ccccc3)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 5-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 32% yield: mp 166-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=2.7 Hz, 1H), 7.48-7.22 (m, 11H), 6.61 (d, J=9.9 Hz, 1H), 6.45 (t, J=5.4 Hz, 1H), 4.98 (s, 2H), 4.56 (d, J=5.4 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 158.7, 153.3, 152.1, 143.3, 137.8, 136.1, 135.5, 128.7, 128.6, 127.9, 127.8, 127.6, 121.7, 112.0, 71.3, 44.0, 17.3; MS (ES+) m/z 432.2 (M+1).