Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9]O)[CH:5]=1)([O-:3])=[O:2].O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:9][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc(CO)n[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CCl)n[nH]1

Procedure:
(5-Nitro-1H-pyrazol-3-yl)methanol (524 mg, 3.66 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 3-(chloromethyl)-5-nitro-1H-pyrazole. Then following General Procedure A, the title compound (515 mg, 49%) was prepared from 2-amino-4-chlorobenzenethiol (161 mg, 1.01 mmol), crude 3-(chloromethyl)-5-nitro-1H-pyrazole, K2CO3 (468 mg, 3.39 mmol) in DMF (3 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccc(Br)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a mixture of 4-chlorobromobenzene (0.53 g, 2.75 mmol) and 3-(R)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) in toluene (20 mL) was added tris(dibenzylideneacetone) dipalladium(0) (0.029 g, 0.032 mmol), BINAP (0.058 g, 0.093 mmol) and sodium-t-butoxide (1.01 g, 10.5 mmol). The resulting mixture was heated 110° C. for 20 h. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Column chromatography (10% ethyl acetate/hexane) provided the title compound.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=O)[CH2:16][CH2:15]2.Cl.O1CCOCC1>C(O)(=O)C>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:17]3[CH:18]4[CH2:21][CH2:22][N:14]([CH2:15][C:16]=3[C:8]=2[CH:7]=1)[CH2:20][CH2:19]4)(=[O:5])=[O:4]
Reactant: O=C1CCN2CCC1CC2
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 80 °C

Procedure:
A mixture of (4-(methylsulfonyl)phenyl)hydrazine hydrochloride (1105 mg, 5.0 mmol; Acros), 1-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol; Example 2A), 4 N HCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and acetic acid (15 mL) was heated to 80° C. overnight (16 hours), then cooled to room temperature. The solvent was removed, and the residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated in vacuo and purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.05-2.14 (m, 4H), 3.02-3.15 (m, 6H), 3.20-3.28 (m, 2H), 4.29 (s, 2H), 7.47 (d, J=8 Hz, 1H), 7.57-7.62 (m, 1H), 7.95 (d, J=1 Hz, 1H); MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:51][CH2:52][CH3:53])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3]>C(O)(=O)C>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:51][CH2:52][CH3:53])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3]
Reactant: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 101.7 %

Procedure:
Following a procedure similar to that described in Example 35(c), 1.23 g of ethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (b) above] were treated with 75% v/v aqueous acetic acid, to give 0.82 g of the title compound as an amorphous solid.
Reaction SMILES: [ClH:1].[SH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[C:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:4]1=[O:17].CN(C)C.[CH3:22][S:23]COS([O-])(=O)=S.[OH-].[Na+]>ClCCl>[ClH:1].[CH3:22][S:23][S:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[C:10][CH2:11][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:4]1=[O:17]
Reactant: CSCOS(=O)([O-])=S
Reactant: O=C1[C@H](S)CCN1CC#CCN1CCCC1
Agent: CN(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CSS[C@@H]1CCN(CC#CCN2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 430 mg of (R)-3-mercapto-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone hydrochloride in 20 ml of dichloromethane was cooled to 0° C. in an ice bath. Successively, 50 μl of trimethylamine and 0.5 ml of methylthiomethylthiosulfate were added and the resulting solution was stirred at room temperature for 30 minutes. A 1N sodium hydroxide solution (2 ml) was added and the resulting mixture was washed with saturated aqueous sodium chloride, dried and concentrated in vacuo. The residue was purified by chromatography (alumina) and the eluent containing the product band was acidified with an excess of 1.4N methanolic hydrogen chloride to give 0.41 g of the desired compound as a pale yellow oil, [α]D26 =+23° (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24]CN[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([N:7]1[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:24][CH2:8]1)=[O:6]
Reactant: CNC(=O)c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccnc(Cl)c2)CC1

Procedure:
2-Chloroisonicotinic acid (12-2, 250 mg, 1.59 mmole), tert-butylpiperazine-1-carboxylate (355 mg, 1.9 mmole), EDC (365 mg, 1.9 mmole), and HOBt (257 mg, 1.9 mmole) were combined in dry DMF (10 mL). To this was added Et3N (0.55 mL, 3.97 mmole) at RT. After 18 hr the mixture was diluted with H2O and extracted with EtOAc (4×). The combined organic layers were washed with H2O, brine; then dried (MgSO4), filtered, and concentrated to give the titled compound as an amber oil which was used immediately in the next step.
Reaction SMILES: C([O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])=[CH:11][CH:10]=1)[CH3:8])(=O)CCC.[BH4-].[Na+].[CH2:23](O)C>>[O:18]1[CH2:19][CH2:20][CH2:23][CH2:17][CH:16]1[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([OH:6])[CH3:8])=[CH:14][CH:13]=1
Reactant: CCO
Reactant: CCCC(=O)OC(C)c1ccc(OC(C)OCC)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ccc(OC2CCCCO2)cc1
Yield: 88 %

Procedure:
In 200 ml of ethanol was dissolved 22.0 g (0.1 mole) of 4-(tetrahydro-2-pyranyloxy)acetophenone obtained in Example 4 (i), to which 2.3 g (58 millimoles) of NaBH4 was added, and the mixture was subjected to reaction for 3 hours at 25° C. After ethanol was distilled under reduced pressure, 200 ml of ethanol was added thereto, and it was washed with diluted hydrochloric acid, then water and finally an aqueous solution of sodium hydrogencarbonate. The resulting ether layer was dried with anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure to give 19.5 g of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethanol (yield: 88%).
Reaction SMILES: [OH-].[Na+:2].[F:3][C:4]([F:42])([F:41])[C:5]1[CH:6]=[C:7]([S:15]([NH:18][C:19]2[S:20][C:21]3[CH2:22][N:23]([C:28]4[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:29]=4[C:30]([NH2:32])=[O:31])[CH2:24][CH2:25][C:26]=3[N:27]=2)(=[O:17])=[O:16])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CCO>[Na+:2].[F:42][C:4]([F:3])([F:41])[C:5]1[CH:6]=[C:7]([S:15]([NH:18][C:19]2[S:20][C:21]3[CH2:22][N:23]([C:28]4[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][C:29]=4[C:30]([NH-:32])=[O:31])[CH2:24][CH2:25][C:26]=3[N:27]=2)(=[O:16])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N1CCc2nc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)sc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: [NH-]C(=O)c1ccc(C(F)(F)F)cc1N1CCc2nc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)sc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.9 ml of an aqueous 0.1 M NaOH solution are added to a solution of 118 mg of 2-[2-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-6,7-dihydro-4H-thiazolo-[5,4-c]pyridin-5-yl]-4-trifluoromethyl-benzamide in 10 ml of EtOH, and the mixture obtained is stirred at RT for 5 minutes. From the mixture obtained solvent is evaporated and the evaporation residue obtained is subjected to lyophilisation. [2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-6,7-dihydro-4H-thiazolo-[5,4-c]pyridin-5-yl]-4-trifluoromethyl-benzamide sodium salt is obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][C:6]([OH:8])=O)[CH3:3].[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:6](=[O:8])[CH2:5][O:4][CH2:2][CH3:3])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CCOCC(=O)O
Agent: Cl
Product: CCOCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 32.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-ethoxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 121, (2S,4R)-4-benzyl-1-(2-ethoxyacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (9.4 mg, 32.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.99 (s, 1H), 7.55-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.47 (m, 1H), 4.06 (d, 2H), 3.60-3.64 (m, 1H), 3.47-3.53 (m, 2H), 3.18-3.22 (m, 1H), 2.50-2.89 (m, 3H), 1.90 (m, 2H), 1.08 (m, 3H). MS (EI) for C28H29FN2O4. found 477.5 (MH+).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1=[O:14])=[CH2:2].[C:15](#[N:18])[CH:16]=[CH2:17].C1(C=CC(O)=CC=1)O.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.CN(C)C=O>[C:15]([CH2:16][CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][CH2:4][O:3][CH:1]=[CH2:2])[C:7]1=[O:14])#[N:18]
Reactant: C=COCCN1C(=O)NC(C)(C)C1=O
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: C=COCCN1C(=O)N(CCC#N)C(C)(C)C1=O

Procedure:
A mixture of 237.8 g (1.2 mols) of 3-(2-vinyloxyethyl)-5,5-dimethylhydantoin, prepared as described in Example 1, 79.6 g (1.2 mols+20% excess) of acrylonitrile, 0.5 g of hydroquinone, 2.4 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol and 360 ml of dimethylformamide is allowed to react for 27 hours at 81°-85° C. The solution is then concentrated on a rotary evaporator at 90° C. under vacuum from a waterpump and the residue is dried to constant weight at 90° C. and 13.3 Pa. 300.4 g (99.6% of theory) of a dark brown, crystalline crude product are obtained and are purified by distillation. 260.8 g (86.5% of theory) of a crystalline distillate boiling at 147°-150° C. are obtained. After recrystallisation from ether, the product melts at 54.8°-55.5° C.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][CH2:24][CH2:25][N:26]([CH2:34][CH2:35][O:36][CH3:37])[C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:37][O:36][CH2:35][CH2:34][N:26]([CH2:25][CH2:24][O:23][CH3:22])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:7]2[N:8]=[CH:9][C:4]3[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:5]=3[N:6]=2)=[N:31][CH:32]=1
Reactant: COCCN(CCOC)c1ccc(N)nc1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: COCCN(CCOC)c1ccc(Nc2ncc3c(C)c(Br)c(=O)n(C4CCCC4)c3n2)nc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.4 g, 1.08 mmol) and N5,N5-Bis-(2-methoxy-ethyl)-pyridine-2,5-diamine (0.5 g, 2.2 mmol) were combined in toluene (3.5 mL) and heated to 110° C. After 5 h the reaction mixture was allowed to cool and the crude product was directly chromatographed on silica gel eluting with a gradient of 25% to 100% ethyl acetate in hexanes to provide 2-{5-[bis-(2-methoxy-ethyl)-amino]-pyridin-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.49 g, 85%) as an orange gum. mp 94-95° C. MS (APCI); M++1: Calc'd, 530.2. Found 530.1. Anal. Calc'd for C24H32N6O3Br10.13H2O: C, 54.00; H, 5.90; N, 15.74. Found; C, 53.61; H, 5.68; N, 15.60.
Reaction SMILES: C[O:2][CH2:3][CH2:4][C@H:5]([C:32]([F:35])([F:34])[F:33])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:9][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][CH2:3][CH2:4][C@H:5]([C:32]([F:34])([F:35])[F:33])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:9][CH:8]=1
Reactant: COCC[C@@H](Oc1ccc(NC(=O)C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Nc3ccc(O[C@H](CCO)C(F)(F)F)cc3)CC2)cc1
Yield: 71.5 %

Procedure:
1-(Toluene-4-sulfonyl)-piperidine-4-carboxylic acid [4-((R)-3-methoxy-1-trifluoromethyl-propoxy)-phenyl]-amide (0.105 g), product of example 59), in methylene chloride (2 ml) was treated at RT and under an argon atmosphere with BBr3 (0.5 molar, 1 ml) for 2 h. The mixture was then partitioned between diethyl ether and aqueous 1N HCL, the layers were separated, the organic layer was dried over sodium sulphate, and evaporated off to give the desired 1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid [4-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-phenyl]-amide (0.073 g) as light brown crystalline solid. MS (ESI): 501.2 (MH+).
Reaction SMILES: C(O[C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[CH:11][C:10]=1[F:33])C1C=CC=CC=1.[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][OH:39]>>[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][O:39][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[CH:11][C:10]=1[F:33]
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCc4ccccc4)c(F)c3)nc2cn1
Reactant: OCC1CC1(F)F
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4(F)F)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (2,2-difluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:22]2[N:23]=[C:24]([NH:27][CH:28]=[O:29])[S:25][CH:26]=2)[C:19]([OH:21])=O)=[O:14])[CH:7]=1.[NH2:30][CH:31]1[C:49](=[O:50])[N:33]2[C:34]([C:46]([OH:48])=[O:47])=[C:35]([CH2:38][S:39][C:40]3[N:44]([CH3:45])[N:43]=[N:42][N:41]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:22]2[N:23]=[C:24]([NH:27][CH:28]=[O:29])[S:25][CH:26]=2)[C:19]([NH:30][CH:31]2[C:49](=[O:50])[N:33]3[C:34]([C:46]([OH:48])=[O:47])=[C:35]([CH2:38][S:39][C:40]4[N:44]([CH3:45])[N:43]=[N:42][N:41]=4)[CH2:36][S:37][C@H:32]23)=[O:21])=[O:14])[CH:7]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCC(=O)Nc2cccnc2)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cccnc3)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 40 °C

Procedure:
A mixture of phosphorus oxychloride (1.6 g.) and N,N-dimethylformamide (31 ml.) was warmed at 40° C. for 30 minutes followed by cooling to -10° C. To the mixture was added 2-[N-(3-pyridyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (3.1 g.) followed by stirring for an hour at -10° to -7° C. On the other hand, a mixture of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.2 g.) and trimethylsilylacetamide (7 g.) in methylene chloride (60 ml.) was stirred for 30 minutes at room temperature and then cooled to -15° C. To the mixture was added the above obtained dimethylformamide mixture followed by stirring for 1.5 hours at -15° to -10° C. To the reaction mixture were added ice-cold water and sodium bicarbonate. The aqueous layer (pH 7 to 8) was separated and washed with ethyl acetate and then thereto was added ethyl acetate. After the pH was adjusted to 3 to 4 with 10% hydrochloric acid, the precipitates were collected and then dissolved in an aqueous solution of sodium bicarbonate. The resulting mixture was treated with activated charcoal and the aqueous layer was separated and then adjusted to pH 3 to 4 with 10% hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([O:28]C)=[O:27])=[CH:23]2)=[CH:18][CH:17]=1>CCO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([OH:28])=[O:27])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc4ccc(C(=O)O)cc4c3)c2cc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 7-(6,7-dimethoxyquinolin-4-yloxy)-2-naphthoate (Step c, 0.809 g, 2.08 mmol) in EtOH (10 mL), 1N NaOH (3 mL) was added. The solution was stirred at 70° C. for 2 h. The reaction was cooled to RT and concentrated in vacuo. The crude material was taken up in water (50 mL) and acidified to pH=3 with 1N HCl. The solid was filtered and dried in vacuo. MS (ESI, pos. ion) m/z: 376.1 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[C:17]([C:20]4[CH:25]=[CH:24][NH:23][C:22](=O)[CH:21]=4)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:31]1C=C(B(O)O)C=[CH:33][N:32]=1.N1(C2C=CC(N)=CC=2)CCOCC1.CC([O-])(C)C.[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][N:32]([CH3:33])[C:22]1[CH:21]=[C:20]([C:17]2[N:16]3[CH:27]=[CH:28][N:29]=[C:15]3[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)=[N:19][CH:18]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: O=c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Nc1ccc(N2CCOCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)ccn1

Procedure:
In the same way as described for Compound 85, step 1, using 2-fluoropyridine-4-boronic acid (0.047 g, 0.337 mmol), 5-bromo-imidazo[1,2-a]pyrazin-8-yl)-4-morpholin-4-yl-phenylamine (0.105 g, 0.281 mmol), Pd(PPh3)4 (32 mg, 0.0281 mmol) and NaOtBu (0.108 g, 1.12 mmol) in N,N-dimethylformamide/water (7 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford the title compound containing some side products. Additional purification by reverse phase prep HPLC affords the title compound as a yellow solid (18 mg, 16%). LCMS: Rt 1.99 min (98%), m/z (APCI) 416 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.09-3.13 (10H, m), 3.78 (4H, m), 6.89 (2H, m), 6.97 (2H, d), 7.59 (1H, s), 7.72 (1H, s), 7.93 (2H, d), 8.09 (1H, s), 8.12 (1H, d), 9.60 (1H, s).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:28].[Na+]>CO.C(OCC)(=O)C.O>[F:13][C:12]1[CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[N:21]3)[O:16][C:15]2=[O:25])[CH:9]=[C:8]([F:26])[C:7]=1[C:4]1[CH2:5][CH2:6][S:1](=[O:28])[CH2:2][CH:3]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCSCC2)c(F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCS(=O)CC2)c(F)c1
Reaction time: 3 h
Yield: 76.1 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (Example 86; 0.86 g, 2.3 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 20 ml) at ambient temperature. Sodium periodate (0.50 g, 2.4 mmol) in water (10 ml) was added dropwise, and the mixture stirred for 3 hours. Precipitated salts were removed by filtration and washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate and concentrated to dryness. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title product (0.69 g). MS (ESP): 395 (MH+) for C17H16F2N4O3S
Reaction SMILES: [CH3:1][C:2]1[C@:8]([OH:17])(/[CH:9]=[CH:10]/[C:11](/[CH3:16])=[CH:12]\[C:13]([OH:15])=[O:14])[C:7]([CH3:19])([CH3:18])[CH2:6][C:4](=[O:5])[CH:3]=1.[OH-].[K+].N.C([O-])(=O)/C=C/C=C/C.[K+]>O>[CH3:1][C:2]1[C:8]([OH:17])(/[CH:9]=[CH:10]/[C:11](/[CH3:16])=[CH:12]\[C:13]([OH:15])=[O:14])[C:7]([CH3:19])([CH3:18])[CH2:6][C:4](=[O:5])[CH:3]=1
Reactant: CC1=CC(=O)CC(C)(C)[C@@]1(O)/C=C/C(C)=C\C(=O)O
Agent: C/C=C/C=C/C(=O)[O-]
Agent: N
Agent: [K+]
Solvent: O
Product: CC1=CC(=O)CC(C)(C)C1(O)/C=C/C(C)=C\C(=O)O

Procedure:
(S)-(+)-Abscisic acid (2.64 g of 95% purity) was suspended in 15 mL of deionized water containing 50 mg of Tween 20. One quarter of the theoretical amount of potassium hydroxide (250 microL of 10.0 molar aqueous solution) was added. The remainder of the neutralization was then carried out with concentrated aqueous ammonia solution, to give a clear solution of pH 7.1. Preservative (63 mg of potassium sorbate) was added, and it quickly dissolved. The solution was made up to 25 mL final volume to give a 10% by weight aqueous composition of abscisic acid as a mixture of the ammonium and potassium salts.