Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][CH2:17][C:3]1=2.C[O-].[Na+].[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>CO>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[C:15]1[C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][N:7]3[C:2](=[O:1])[C:3]=2[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CCC3
Reactant: Cc1ccccc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1C=C1CCc2c1nc1ccc(C(=O)O)cn1c2=O
Yield: 42.2 %

Procedure:
1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.12 g) in methanol (145 ml) containing 2.9 g of sodium methoxide was reacted with 4.86 g of 2-methyl-benzaldehyde under stirring at reflux temperature for 144 hours. After cooling and concentration in vacuo to a small volume, the precipitate was filtered and treated with acetic acid and then with water: the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2 /methanol and then from dioxane to give 1.9 g of 3-(2-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 300°-302° C., NMR (CF3COOD) δ ppm: 2.49 (s) (3H, --CH3), 3.36 (s) (4H, cyclopentane protons), 7.42 (m) (3H, phenyl protons), 7.64 (m) (1H, phenyl proton), 7.81 (bs) (1H, =CH--), 8.40 (d) (1H, C-5 proton), 9.11 (d d) (1H, C-6 proton), 10.23 (d) (1H, C-8 proton).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[CH3:32][OH:33].Cl>C(OCC)C>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[C:18]([C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=2)[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:33][CH3:32])[N:7]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: CO
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Agent: Cl
Solvent: CCOCC
Product: COc1nccc(Nc2cc(NC(=O)c3cccc4c3oc3ccccc34)ccc2C)n1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-4-[5-(4-dibenzofuranylcarbonylamino)-2-methylanilino]pyrimidine (0.1 g), methanol (2 ml) and a 2M solution of hydrogen chloride in diethyl ether (0.5 ml) was stirred and heated to 70° C. for 24 hours. The reaction was evaporated and the residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.025 g); NMR Spectrum: (DMSOd6) 2.26 (s, 3H), 3.85 (s, 3H), 6.36 (d, 1H), 7.34 (m, 1H), 7.46-7.7 (m, 4H), 7.87 (m, 1H), 7.92 (m, 1H), 8.01 (s, 1H), 8.09 (d, 1H), 8.29 (d, 1H), 8.4 (d, 1H), 9.09 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=3)[NH:11][C:10]=2[CH3:21])=[CH:4][CH:3]=1.[CH3:22][Si](Cl)(C)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:22])=[O:19])[CH:16]=3)[NH:11][C:10]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1Sc1ccc(Cl)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Reaction time: 8 h

Procedure:
To a solution/suspension of the product from part (i) (1 g) in methanol (50 ml) was added trimethylsilylchloride (12.6 ml). After stirring at room temperture overnight the mixture was concentrated in vacuo to give sub-title compound in quantitative yield.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[C:4]1=[O:10])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].ClCCl>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:10])[C:5]1=[O:9])[CH3:19]
Reactant: CCN1CCNC(=O)C1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CN1CCN(CC)C(=O)C1=O
Yield: 72 %

Procedure:
As described for example 119a, 1-ethyl-piperazine-2,3-dione was reacted with sodium hydride followed by reaction with ethyl bromoacetate. Aqueous workup followed by chromatography (SiO2, dichloromethane:methanol=100:0 to 94:4) afforded the title compound as a light yellow oil (yield: 72%). MS: m/e=229.4 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[NH:23][C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:25](Cl)[N:26]=1)C1C=CC=CC=1.C(O)=O.[Cl-]>CO.[Pd]>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:24]2[NH:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:26][CH:25]=2)=[CH:30][CH:31]=1
Reactant: CC1(C)OCCn2c1nc(-c1nc(Cl)c(Cc3ccc(F)cc3)[nH]1)c(OCc1ccccc1)c2=O
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Solvent: O=CO
Product: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)[nH]1)c(O)c2=O
Temperature: 40 °C
Reaction time: 5 h
Yield: 35.4 %

Procedure:
To a solution of 3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-1H-imidazol-2-yl)-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (0.03 g, 0.061 mmol, 1.0 equiv) in MeOH (3 mL) under a nitrogen atmosphere, was added formic acid (0.1 mL, 2.61 mmol, 43 equiv) and 10% Pd/C (0.065 g, 0.061 mmol, 1.0 equiv). The reaction was stirred for 5 h after which LCMS analysis indicated complete benzyl hydrogenolysis but no chloride reduction. The reaction was warmed to 40° C. (oil bath) and stirred 2 h. LCMS analysis now indicated complete chloride reduction. The reaction was cooled to ambient temperature and stirred a further 16 h. The reaction was then filtered through celite and concentrated in vacuo. The residue was added to saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×5). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by silica gel chromatography (7% MeOH/CH2Cl2) to provide the title compound (0.008 g, 36% yield) as a tan solid. 1H NMR (400 MHz, d7-DMF) δ ppm (major imidazole tautomer) 13.14 (s, 1H), 7.48-7.58 (m, 2H), 7.39 (s, 1H), 7.29 (t, J=8.56 Hz, 2H), 4.21-4.25 (m, 2H), 4.15 (s, 2H), 4.08 (t, J=5.16 Hz, 2H), 1.74 (s, 6H); LCMS (ES+, (M+H)+) m/z 371.17.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=1.[CH3:20][CH:21]([NH:23][C:24](=[O:32])OC1C=CC=CC=1)[CH3:22]>CN(C)C=O>[CH3:20][CH:21]([NH:23][C:24]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([NH:3][C:24]([NH:23][CH:21]([CH3:20])[CH3:22])=[O:32])[N:9]=[CH:8][N:7]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:32])[CH3:22]
Reactant: Nc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Reactant: CC(C)NC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1cc(Nc2ccc3c(ccn3C(=O)NC(C)C)c2)ncn1
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
Sodium hydride (48 mg, 1.2 mmol) was suspended in N,N-dimethylformamide (2.5 ml); 6-amino-4-(1H-5-indolylamino)pyrimidine (225.3 mg, 1.0 mmol) was added thereto at room temperature under nitrogen stream; the reaction mixture was stirred for 30 minutes; phenyl N-(2-propyl)carbamate (215 mg, 1.2 mmol) was added thereto; and the reaction mixture was stirred overnight. The reaction mixture was partitioned between a solvent mixture of ethyl acetate-tetrahydrofuran (1:1) and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; ethyl acetate); eluted fractions were concentrated; ethyl acetate was added to the residue to crystallize; and the crystals were filtered off, and dried under aeration to yield the title compound (31.3 mg, 0.079 mmol, 7.9%) as white crystals.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=3)=[CH:16][CH:15]=2)[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccncc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In N,N-dimethylformamide (40 ml), 4-(4-pyridyl)benzoic acid hydrochloride (654 mg) and tert-butyl 1-piperazinecarboxylate (569 mg) were suspended. To the resulting suspension, 1-hydroxybenzotriazole (374 mg) and N-methylmorpholine (336 μl) were added. The resulting mixture was ice cooled, followed by the addition of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (796 mg). After stirring at room temperature for 7 hours, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (2% methanol—dichloromethane), followed by washing with hexane, whereby the title compound (905 mg, 89%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[NH:8]2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>C(Cl)Cl>[Si:23]([O:13][CH2:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([N+:16]([O-:18])=[O:17])=[C:2]([F:1])[CH:10]=2)([CH3:15])[CH3:14])([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(CO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a stirred solution of 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (10.0 g) in CH2Cl2 was added TBSCl (8.9 g), imidazole (8.1 g, 0.12 mol) at room temperature. The mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole (5.3 g, 38%). 1H NMR (300 MHz, CDCl3) 9.51 (s, 1H), 8.31 (d, J=7.5 Hz, 1H), 7.02 (d, J=11.7 Hz, 1H), 6.32 (s, 1H), 3.63 (s, 2H), 1.35 (s, 6H), 0.99 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[CH:4]/[C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].C(O)(=O)C.C(N)=[NH:18]>O>[CH3:8][O:7][CH:6]([O:9][CH3:10])[C:5]1[CH:4]=[CH:3][N:2]=[CH:1][N:18]=1
Reactant: N=CN
Reactant: COC(OC)C(=O)/C=C/N(C)C
Solvent: CC(=O)O
Solvent: O
Product: COC(OC)c1ccncn1
Temperature: 120 °C
Yield: 70.3 %

Procedure:
A mixture of (E)-4-dimethylamino-1,1-dimethoxy-but-3-en-2-one (49.6 g, 286 mmol) and formamidine acetate (44.7 g, 429 mmol) was heated at 120° C. for 4 h. After cooling to room temperature the mixture was poured into water and extracted with dichloromethane. The combined organic extracts were then dried over sodium sulfate, filtered and evaporated. Purification by distillation afforded the title product (31 g, 70%) as a colourless liquid. Bp 59-60° C. at 1.3 mbar. MS: m/e=155.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
3-Nitro-1-octyl-1H-pyrazole (134 mg, 0.60 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-octyl-1H-pyrazol-3-ylamine (48 mg, 41%) as a golden oil: ESI-LRMS m/e calcd for C11H21N3 [M+] 195.18, found 196.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[N:10]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2cc(C#N)ccc2N(Cc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a solution of (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (820 mg, 3 mmol), prepared as described in Example 1C, and 3-chloro benzaldehyde (0.34 mL, 3 mmol) in DCE (10 mL) was added NaBH(OAc)3 (1.78 g, 8.4 mmol), followed by acetic acid (0-34 mL, 6 mmol). The reaction was stirred at RT for 16 h, then quenched with saturated aqueous NaHCO3, extracted with CH2Cl2 (30 mL×3). The organic extracts were washed with water, saturated aqueous NaCl, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (10-50%) in hexanes to give the title compound (571 mg, 48%) as a foam.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([C@@H:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]2[CH2:16][OH:17])=[C:8]([O:18][CH3:19])[CH:7]=[C:6]([O:20][CH3:21])[C:5]=1[C:22](=[O:24])[CH3:23].[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](OC)=O.Cl>CN(C=O)C.CO>[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]1[O:3][C:4]2[C:5]([C:22](=[O:24])[CH:23]=1)=[C:6]([O:20][CH3:21])[CH:7]=[C:8]([O:18][CH3:19])[C:9]=2[C@@H:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]1[CH2:16][OH:17]
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (50%, 2.17 g, 45.3 mmol) was added in portions to a solution of compound of example 6 (2.8 g, 9 mmol) in dry DMF (30 mL) at 0° C., under nitrogen atmosphere and with stirring. After 10 min., methyl 2-chlorobenzoate (5.09 g, 29.9 mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. Methanol was added carefully below 20° C. The reaction mixture was poured over crushed ice (300 g), acidified with 1:1 HCl (pH 2) and extracted using EtOAc (2×100 mL). The aqueous layer was basified using a saturated Na2CO3 (pH 10) and extracted using CHCl3 (3×200 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated. To the residue, conc. HCl (25 mL) was added and stirred at room temperature for 2 h. The reaction mixture was poured over crushed ice (300 g) and made basic using a saturated aqueous Na2CO3 solution. The mixture was extracted using CHCl3 (3×200 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:38])([F:37])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:36][C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:37])[F:38])=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4′-Trifluoromethoxy-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H25F3O6 [M+NH4]+: 508, [M+Na]+: 513.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:16]=[C:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:13]C=1C(O)=O.CN(C=O)C>C1COCC1.CN(C=O)C>[Cl:7][C:8]1[CH:16]=[C:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
Oxalyl chloride (0.63 g) in dry THF (5 ml) was added dropwise over 5 minutes to a solution of 2-chloro-4-(2'-methylpropionamido)benzoic acid (1.0 g) in dry THF (5 ml) at room temperature. After completion of the addition, dry DMF (1 drop) was added causing vigorous effervescence and a slight temperature rise. After stirring for 4 hours and addition of a further drop of DMF, the THF was evaporated to yield 2-chloro-4-(2'-methylpropionamido)benzoyl chloride as a viscous brown gum which was used without further purification. IR (liquid film): 3320, 3260, 3160, 3070, 1780, 1710, 1680, cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][S:15]([NH:18][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:17])=[O:16]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
3-(tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv) was dissolved in DCM (100 mL). Then methanesulfonamide (1.43 g, 15.1 mmol, 0.7 equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g, 3 mmol, 0.15 equiv) were added to the mixture and stirred for 2 h at r.t. The reaction mixture was cooled down to 0° C. ice water (100 mL) was added. The mixture was stirred for 15 min, separated and the water layer was extracted twice with DCM. The combined organic layer was washed by 5% HCl, brine, dried over Na2SO4, concentrated to give tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate as a gray oil (3.6 g, 90%). ESI-MS (M+H)+: 267.1. 1H NMR (400 MHz, DMSO-d6) δ: 6.91˜6.83 (brs, 1H), 3.36 (s, 3H), 3.19˜3.12 (m, 2H), 2.41 (t, 2H), 1.37 (s, 9H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][S:42]([N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1)(=[O:44])=[O:43]
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.20 g, 0.35 mmol) from Example 2 in CH2Cl2 (20 mL) was added methanesulfonoyl chloride (0.045 g, 0.39 mmol) and DIEA (0.14 mL, 0.80 mmol). The solution was stirred at ambient temperature for 6 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (25 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant to give the title compound as an amorphous solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH:16]=[C:26]3[S:20][C:21](=[S:22])[NH:23][C:24]3=[O:25])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)(C)c1ccc(Sc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Sc2ccc(C=C3SC(=S)NC3=O)cc2)cc1
Yield: 51.9 %

Procedure:
The 4-[4-(t-butyl)phenylthio]benzaldehyde (1.5 g, 5.5 mmol) was coupled with rhodanine (0.87 g, 6.5 mmol) in the presence of sodium acetate (1.64 g, 20 mmol) and acetic acid (80 ml) essentially as previously described to yield 1.1 grams (52.3%) of the title product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc2ncsc2c1
Yield: 75.1 %

Procedure:
A solution of benzothiazole-6-carboxylic acid (4.48 g, 25.0 mmol), tert-butyl carbazate (3.63 g, 27.5 mmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (5.75 g, 30.0 mmol) and 1-hydroxybenzotriazole (4.05 g, 30.0 mmol) in N,N-dimethylformamide (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/tetrahydrofuran=2/1), and crystallized from hexane/acetone to give the title compound (5.51 g, yield 75%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].[H-].[Na+].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cl)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Bromonicotinic acid (1 g, 4.950 mmol) is placed in a 100 ml round bottomed flask and purged with Argon. Dry THF (20 ml) is added and the resulting solution is treated with NaH (60% dispersed in mineral oil) (0.202 g, 5.049 mmol) over a period of 5 minutes. The reaction mixture is stirred at room temperature for 10 minutes and then oxalyl chloride (0.453 ml, 5.198 mmol) is added slowly over 5 minutes followed by dry DMF (10 ul). The reaction mixture is stirred for a further 5 minutes, filtered through filter paper, concentrated in vacuo and dried under vacuum to afford the title compound.