Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 3-fluorophenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz): δ 1.294 (s, 9H), 1.756 (bs, 2H), 2.015 (bs, 2H), 2.809 (bs, 3H), 3.447 (bs, 2H), 6.480 (s, 1H), 6.713 (d, J=10.1 Hz, 1H), 7.245 (m, 4H), 7.557 (m, 1H), 7.624 (t, J=7.6 Hz, 1H), 7.735 (m, 2H), 7.986 (d, J=10.1 Hz, 1H). Mass spectrum (ESI): 523.5 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5](=[NH:14])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].Cl[CH2:19][CH:20]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[CH:19]=[CH:20][N:14]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=CCCl
Reactant: Cc1ccccc1NC(=N)c1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccccc1-n1ccnc1-c1cccc(I)c1

Procedure:
To a 500 mL round bottom flask was added 3-iodo-N-(o-tolyl)benzimidamide (7.77 g, 23.11 mmol), 2-chloroacetaldehyde (5.87 ml, 46.2 mmol), sodium bicarbonate (3.88 g, 46.2 mmol), and 100 mL 2-propanol. The reaction mixture was heated to reflux under nitrogen for 5 hours. The reaction mixture was concentrated, water was added, and the mixture extracted three times with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 40 and 50% ethyl acetate/hexane (4.6 g, 55%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13])[CH:2]=[CH2:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C.Cl>ClCCCl>[CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc(N)c1C(=O)c1ccc(C(C)C)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CCc1c(O)ccc(NCc2ccccc2)c1C(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 39 mg (0.13 mmol) (2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone and 13.34 μl (13 mmol) benzaldehyde in 1.3 ml 1,2-dichlorethane and 0.3 g molecular sieves (4 Å pore size) are added after 1 h 13 mg (0.18 mmol) sodium cyanoborohydride and 7.55 μl acetic acid (0.13 mmol). After stirring for 16 h at r.t. 1 M hydrochloric acid is added to destroy the excess of hydride equivalents. By adding 1 M NaOH the mixture is basified. The crude product obtained by extraction with dichloromethane is purified by reversed phase preparative chromatography.
Reaction SMILES: C(O[C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:26])([F:25])[F:24])[CH:20]=3)[O:15][C:14]([CH3:28])([CH3:27])[C@H:13]2[OH:29])=[N:6][S:7](=[O:10])(=[O:9])[N:8]=1)C.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[CH3:31][CH:30]([NH:33][C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:24])([F:25])[F:26])[CH:20]=3)[O:15][C:14]([CH3:27])([CH3:28])[C@H:13]2[OH:29])=[N:6][S:7](=[O:9])(=[O:10])[N:8]=1)[CH3:32]
Reactant: CC(C)N
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Product: CC(C)NC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O

Procedure:
In a method similar to Example 5, the product of Example 1, Step 2 (0.200 g, 0.457 mmol) was converted to the title compound with isopropylamine (0.64 mL, 7.5 mmol) in 1 hour to give 0.180 g (87%) of a white solid: mp 296-298 (dec); 1H NMR (DMSO-D6): δ 8.90 (br s, 1H), 8.30 (br s, 1H), 7.26 (s, 1H), 7.23 (d, 1H), 6.91 (d, 1H), 6.00 (d, 1H), 4.78 (d, 1H), 3.86 (br t, 1H), 3.63 (dd, 1H), 1.40 (s, 3H), 1.24 (dd, 6H), 1.16 (s, 3H); IR (KBr) 3300, 1620 cm-1 ; MS (m/z) 451 (MH+, 100%); [α]D25 =-73.5 (THF)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH2:12]([NH2:16])[CH:13]([CH3:15])[CH3:14]>O.C(O)C>[CH3:8][C:6]1[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]2=[C:2]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: CC(C)CN
Solvent: CCO
Solvent: O
Product: Cc1cc(NCC(C)C)c2[nH]ncc2n1
Yield: 40.8 %

Procedure:
A mixture of 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (1.0 g, 0.006 mole) and isobutylamine (58 g) in water (100 ml) and ethanol (50 ml) was heated under reflux for 10 days. The reaction mixture was cooled and evaporated to dryness. The oily residue was basified to pH8-9 with 10% sodium carbonate solution. The residue was extracted with ethyl acetate (3×100 ml), dried (Na2SO4) and evaporated to dryness to give a yellow oil. This was purified by column chromatography on alumina, and eluted with chloroform/methanol to give the desired compound as a white solid (500 mg). m.p. 162°-164° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([CH3:11])=[CH2:10])=[CH:4][CH:3]=1.[CH2:13](Cl)[CH:14]=[CH2:15].P(=O)(O)(O)O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(OC)(C)C>[CH2:15]([O:12][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:9]([CH3:11])=[CH2:10])[CH:14]=[CH2:13]
Reactant: C=C(C)C(O)c1ccc(C)cc1
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P(O)(O)O
Agent: [I-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=CCOC(C(=C)C)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 80.2 %

Procedure:
Solid sodium tert-butylate (66.65 g, 0.589 mol) was dissolved under nitrogen in dry THF (350 ml) and 1-(4-methylphenyl)-2-methyl-2-propen-1-ol (41.16 g, 0.239 mol) in dry THF (25 ml) was added in 15 minutes without external cooling. The reaction was further stirred at room temperature for 50 minutes. Tetra butyl ammonium iodide (5.04 g, 0.014 mol) was added followed by allyl chloride (40 g, 0.518 mol) in 25 minutes (exothermic to 47° C.). The reaction was stirred for 24 hours, before adding more tetra butyl ammonium iodide (2.30 g, 0.006 mol) and allyl chloride (9.30 g, 0.120 mol). After stirring for 24 hours at room temperature, the reaction was poured onto ice, diluted with MTBE and acidified with aqueous phosphoric acid. The organic phase was washed with brine, saturated aqueous sodium bicarbonate and brine and dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with MTBE and solvents were removed under vacuum. The product was purified by distillation through a 35-cm Fisher column. 38.78 g of the desired allyl ether were obtained (yield=80%). B.P.=79° C./1.6 mbar
Reaction SMILES: C(OC[O:9][C:10]([C:12]1[N:17]2[C:18](=[O:21])[CH:19]([NH2:20])[C@H:16]2[S:15][CH2:14][C:13]=1[CH:22]=[CH:23][C:24]1[S:28][CH:27]=[N:26][C:25]=1[CH3:29])=[O:11])(=O)C(C)(C)C.[C:30]([NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55](=[N:59][O:60][CH3:61])[C:56](O)=[O:57])[N:54]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:61][O:60][N:59]=[C:55]([C:53]1[N:54]=[C:50]([NH:49][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:51][CH:52]=1)[C:56]([NH:20][CH:19]1[C:18](=[O:21])[N:17]2[C:12]([C:10]([OH:9])=[O:11])=[C:13]([CH:22]=[CH:23][C:24]3[S:28][CH:27]=[N:26][C:25]=3[CH3:29])[CH2:14][S:15][C@H:16]12)=[O:57]
Reactant: Cc1ncsc1C=CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7-Amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (0.229 g) as prepared in Reference Example 1 above was dissolved in methylene chloride (5 ml). The resultant solution was admixed with 2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid (syn-isomer) (0.235 g) and methylene chloride (5 ml). To the mixture obtained were further added pyridine (0.07 ml) and then dropwise phosphorus oxychloride (0.07 ml) at -20° C. The reaction mixture was stirred for 10 minutes at 0° C. and poured into a mixture of ice-water (50 ml) and ethyl acetate (50 ml). After stirring, the organic phase was separated from the aqueous phase and washed with ice-wated and then with ice-cooled aqueous saturated sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified chromatographically on a column of silica gel (Wako gel C-300) (20 g ) as developed with benzene-ethyl acetate (5:1) as the development solvent. 7-[2-Methoxyimino-2(2-tritylaminothiazol-4yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer) pivaloyloxymethyl ester (0.184 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1CCCCC1

Procedure:
The title compound was prepared from N-(t-butoxycarbonyl)D-prolinal and piperidine using the procedure detailed in example 200; MS (ES+), m/e 269 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:16]#[N:17]>CN(C)C=O>[C:16]([C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(F)c(F)c(Br)c1F
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(F)c(C#N)c1F
Yield: 61.8 %

Procedure:
A mixture of 269 g of methyl 3-bromo-2,4,5-trifluorobenzoate, 108 g of copper(I) cyanide and 400 ml of dimethylformamide is heated under reflux for 5 hours. All volatile components are distilled off in vacuo. Fractional distillation of the resulting mixture gives 133 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][C:7](=[O:33])[CH2:8][NH:9][C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.CCN(CC)CC.[C:47]1([CH3:56])[C:48]([C:53](Cl)=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1>C(Cl)Cl>[C:47]1([CH3:56])[C:48]([C:53]([N:9]([CH2:8][C:7](=[O:33])[CH2:6][N:5]2[C:4](=[O:34])[C:3]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]3[C:1]2=[O:39])[C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N(CC(=O)CN1C(=O)c2ccccc2C1=O)[C@@H](c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To 2-[(R)-1-(3-phthalimido-2-oxo-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.88 g, 1.5 mMol) in CH2Cl2 (10 mL) was added Et3N (0.23 mL, 1.6 mMol) and toluoyl chloride (0.21 mL, 1.6 mMol). The reaction was stirred at RT for 18 h, concentrated under vacuum, taken up in EtOAc, washed with 1 N HCl, brine, dried (MgSO4) and evaporated to dryness. Purification by flash chromatography on silica gel (5-15% EtOAc/hexane) followed by trituration with pet. ether, filtration and drying under vacuum gave the title compound (0.89 g, 90%) as a white solid: MS (ES) m/e 661.2 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][C:34]([F:35])([F:36])[F:37])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1OC(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (359 mg) and 37% formalin (0.24 mL) in the same manner as in Example 1 was dissolved in chloroform (10 mL), and triethylamine (0.80 mL) and 3-cyano-4-methoxy-5-trifluoromethoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (j).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1>C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(CNc2ccc(CO)c(F)n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc(C=O)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To [2-fluoro-6-(4-methoxy-benzylamino)-pyridin-3-yl]-methanol (64, 63 g, 240 mmol) in 1.25 L of ethyl acetate, manganese(IV) oxide (210 g, 2.416 mol) was added. The reaction was stirred overnight at room temperature, then filtered through celite and the celite rinsed with ethyl acetate. The combined filtrates were concentrated under vacuum and the resulting solid was triturated with heptane and collected by filtration to provide the desired compound as a white solid (65, 62 g, 238 mmol, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][CH:21]([O:32][NH2:33])[CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>O1CCOCC1>[Si:12]([O:19][CH2:20][CH:21]([O:32][NH:33][C:6]1[N:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[NH:8][CH:9]=[O:10])[CH2:22][CH2:23][P:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:31])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: O=CNc1c(Cl)ncnc1Cl
Reactant: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ON)OCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ONc1ncnc(Cl)c1NC=O)OCC
Temperature: 90 °C
Yield: 28.8 %

Procedure:
A mixture of 4,6-dichloro-5-formamidopyrimidine (0.73 g, 3.8 mmol), diethyl [4-(t-butyldimethylsilyloxy)-3-(aminooxy)butyl]phosphonate (1.35 g, 3.8 mmol) and triethylamine (0.78 ml, 5.7 mmol) in dioxan (20 ml) was heated at 90° C. for 3 hours. After cooling to ambient temperature, the mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel using dichloromethane-methanol (98:2) as eluant to yield the title compound as a oil (0.56 g, 29). IR: υmax (film) 3180, 2940, 2870, 1690, 1635, 1250, 1030, 970, 830, 780 cm-1. 1H NMR: δH (CDCl3) 0.05 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.3 (6H, t, J=7Hz, (OCH2CH3 )2), 1.6-2.3 (4H, m, CH2CH2P), 3.6-4.3 (7H, m, OCH2CH+(OCH2CH3)2), 7.3-10.05 (4H, broad, --NHCHO+--NHO+H-2).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([C:30]([F:33])([F:32])[F:31])[CH:19]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].O[Li].O>CO.O>[F:32][C:30]([F:31])([F:33])[C:20]1[CH:19]=[C:18]([S:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][N:7]3[CH2:8][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]3)=[CH:11][CH:12]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CN(Cc2ccc(CSc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2)C1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)C1CN(Cc2ccc(CSc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzyl]-azetidine-3-carboxylic acid methyl ester (129 mg, 0.2736 mmol, 1 eq.) in a mixture of MeOH (5 mL) and H2O (0.5 mL) is added LiOH—H2O (23 mg, 0.5472 mmol, 2 eq.). The mixture is stirred at room temperature for 3 h. After concentration, the crude product is purified by preparative RP LC-MS to give 1-[4-(2-Trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzyl]-azetidine-3-carboxylic acid: 1H NMR (CD3OD, 400 MHz) δ7.61 (s, 1H), 7.60 (d, 1H), 7.56 (d, 2H), 7.46–7.39 (m, 6H), 7.29 (d, 2H), 4.42 (s, 2H), 4.35 (s, 2H), 4.31 (d, 4H), 3.73–3.61 (m, 1H); MS (ES+): (458.1, M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[O:33])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in Example 13, 300 mg, 0.65 mmol) in ethanol (20 mL) at 25° C. was treated with a solution of potassium hydroxide (109 mg, 1.94 mmol) in water (6 mL). This light yellow solution was stirred at 25° C. for 2 h and then concentrated in vacuo to remove ethanol. The resulting aqueous solution was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/80 hexanes/ethyl acetate plus 1% acetic acid) afforded 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid (226 mg, 80%) as a white solid: mp >200° C.; FAB-HRMS m/e calcd for C24H24N2O4S (M+H)+ 437.1535, found 437.1534.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:15]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ncnc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.13 g, 0.58 mmol, 1.0 eq.) and DMF (3 ml). The mixture was cooled to 0° C. followed by the addition of NaH (0.028 g, 0.70 mmol, 1.2 eq) with stirring. After stirring for 10 minutes SEM-CL (0.106 g, 0.64 mmol, 1.1 eq) was added and the reaction was allowed to warm to room temperature with stirring for 1 hour. The reaction was diluted with ethyl acetate (50 ml), washed (2×) water, (1×) NaHCO3, (2×) 5% LiCl, (1×) brine, and dried over sodium sulfate, and concentrated in vacuo to give 4-chloro-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a cream solid (0.17 g, 84%). MS (ESI) for C15H22ClN3O3Si: 356 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([C:15]4[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH3:22])[CH:16]=4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([O:27]CC)=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+]>Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([C:15]4[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH3:22])[CH:16]=4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)cc(C)n1
Yield: 75.3 %

Procedure:
A suspension of 1.0 g ethyl 1-cyclopropyl-6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 20 ml 1M hydrochloric acid was heated at reflux for 2 hours. The reaction mixture was cooled, poured into saturated sodium acetate and extracted with ethyl acetate. The extract was dried (sodium sulfate) and concentrated, and the residue (0.84 g) was recrystallized from absolute ethanol to give 0.70 g 1-cyclopropyl-6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, colorless needles, m.p. 246°-248.5° C.