Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[C:34]([O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[C:34]([CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31])[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c(Cl)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c(Cl)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:7]([C:8]([NH2:10])=[O:9])[CH:6]=1)C.[CH3:18][O:19][CH2:20][CH2:21]N>>[N+:14]([C:12]1[CH:11]=[C:7]([C:8]([NH:10][CH2:21][CH2:20][O:19][CH3:18])=[O:9])[CH:6]=[C:5]([CH:13]=1)[C:4]([OH:3])=[O:17])([O-:16])=[O:15]
Reactant: COCCN
Reactant: CCOC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Product: COCCNC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.1 %

Procedure:
239.2 g (1 mole) of 5-nitroisophthalamic-acid-monoethylester is dissolved in 444 ml (5 moles) of 2-methoxyethylamine, the temperature rising to 60° C. After stirring for 2 days at room temperature, the mixture is evaporated in vacuum at 70° C., dissolved with 2.4 liters of water, adjusted to a pH of 7 by means of hydrochloric acid, treated with charcoal and then acidified to a pH of 1 with 12 N hydrochloric acid. The precipitate provides 217.6 g (81.1% of theoretical) of 5-nitro-N-(2-methoxyethyl)-isophthalamic acid; m.p.=203°-207° C.
Reaction SMILES: C[O-].[Na+].[N+:4]([CH3:7])([O-:6])=[O:5].[C:8]1([CH2:14][CH:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[N+:4]([CH2:7][CH:15]([OH:16])[CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:6])=[O:5]
Reactant: O=CCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])CC(O)Cc1ccccc1
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
Sodium methoxide (1.1 g) was added to a stirred solution of nitromethane (Aldrich, 12.2 g) in methanol (100 ml) at 0° C. and the mixture stirred for 10 minutes. A solution of phenylacetaldehyde (Aldrich, 24.0 g) in methanol (50 ml) was added dropwise over 15 minutes and the mixture stirred for 45 minutes at 0° C., then brought to room temperature over 1 hour and stirred overnight. The mixture was evaporated in vacuo and the residue taken up in water and extracted with ether. The combined extracts were washed with water and brine and evaporated in vacuo to give the desired product as a yellow oil (29.0 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:21][CH2:22][CH2:23][OH:24]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:21][CH2:22][CH2:23][OH:24])=[CH:3][CH:2]=1
Reactant: Oc1ccnc2ccccc12
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A suspension of quinolin-4-ol (1.35 g, 9.30 mmol), anhydrous potassium carbonate (3.73 g, 26 mmol) and potassium iodide (4.23 g) in anhydrous DMF (8 mL) was stirred at 25° C. for 30 minutes. 3-Chloropropanol (2.93 g, 31 mmol) was added and the reaction was stirred until the starting material was consumed. The reaction was diluted with dichloromethane and extracted with water. The product was obtained as a slightly yellow solid (0.5298 g, 28%) after evaporation of the dichloromethane layer, and was used for the next step without further purification. 1H NMR (400 MHz, CDCl3): 2.09 (2H, m), 3.93 (2H, t, J=5.6 Hz), 4.10 (2H, t, J=5.6 Hz), 4.51 (11H, s), 6.25 (1H, d, J=5.5 Hz), 7.32 (1H, t, J=7.4 Hz), 7.56 (1H, t, J=8.2 Hz), 7.90 (1H, d, J=8.4 Hz), 7.93 (1H, d, J=8.4 Hz), 8.36 (1H, d, J=5.3 Hz).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH2:13]2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:16][CH2:17][C:10]3([CH2:9][NH:8][CH2:12][CH2:11]3)[CH2:13][CH2:14]2)[CH:19]=1
Reactant: C1=C(c2cccnc2)CCC2(C1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1cncc(C2CCC3(CCNC3)CC2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A solution of 2-benzyl-8-(pyridin-3-yl)-2-azaspiro[4.5]dec-7-ene (250 mg, 0.822 mmol, 1.0 eq.) in MeOH (15 ml) was degassed with argon for 15 min, followed by addition of Pd(OH)2 (125 mg, 50% by wt.). The reaction mixture was stirred under H2 balloon pressure for 4.5 h at RT. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield the desired compound as an off-white solid which was used in the next step without further purification. Yield: 93% (165 mg, 0.76 mmol).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:6]1=2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[O:17])=[CH:14][C:6]1=2
Reactant: O=C(O)c1cnc2c(c1)N(Cc1cc(F)ccc1F)CCN2
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)CC1
Yield: 65 %

Procedure:
1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (40 mg) was reacted with 1-methyl piperazine as in General Procedure 8 to give the title compound as an orange foam (65% yield). M.p. (foam), LCMS: m/z=388.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (s, 3H), 2.32-2.38 (m, 4H), 3.41 (t, J=5.0 Hz, 2H), 3.53-3.61 (m, 4H), 3.62-3.65 (m, 2H), 4.44 (s, 2H), 5.07 (bs, 1H), 6.61 (s, 1H), 6.89-6.94 (m, 2H), 6.98-7.04 (m, 1H), 7.59 (d, J=1.5 Hz, 1H).
Reaction SMILES: I[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH:9](/B(O)O)=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>>[CH:9](/[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1)=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=Cc1csc(I)c1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Product: O=Cc1csc(/C=C/c2ccccc2)c1
Yield: 20 %

Procedure:
(E)-5-styrylthiophene-3-carbaldehyde was synthesized from 5-iodo-3-thiophene carboxaldehyde and (E)-styrylboronic acid using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde. The crude product was chromatographed over silica gel (0 to 25% EtOAc in heptane over 30 min) to give (E)-5-styrylthiophene-3-carbaldehyde (0.115 g, 20% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.86 (s, 1H), 7.97 (s, 1H), 7.48 (m, 3H), 7.38 (m, 2H), 7.31 (m, 1H), 7.19 (d, J=16.2 Hz, 1H), 6.99 (d, J=16.2 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>O1CCCC1>[C:1]([N:5]([CH3:29])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)(C)C)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To a solution of methyl 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (115 mg, 0.33 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (65 mg, 2.71 mmol) at 0° C. and then stirred for 10 minutes at room temperature. Methyliodide (185 mg, 1.30 mmol) was then added with stirring, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water (50 mL), adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (3×80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the residue. Purification via Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm] afforded 3-(tert-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (8.20 mg, 7.13%).
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.[NH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11].C(NCC(O)=O)(=O)C.CN(CC(O)=O)CC(O)=O>COCCOC>[C:1]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=C(O)CNCC(=O)O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Agent: CN(CC(=O)O)CC(=O)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 100 °C
Yield: 95 %

Procedure:
The regenerated catalyst precursor was transferred, under CO:H2 pressure, into the autoclave containing CO:H2 (95:5) at 800 psi (5517 kPa), acetamide (VII)(29.5 g, 0.5 mole), 95% paraformaldehyde (34.0 g, 1.08 mole), water (32.2 g, 1.79 mole), and DME (650 mL). A CO:H2 (95:5) atmosphere at 1500 psi (10,345 kPa) was immediately established. This mixture was heated to 100° C. The reaction warmed to 125° C. and was maintained at this temperature for one hour. HPLC analysis of this stream gave a 95% yield of (XVI), 2% (XIV), 2.5% (XVIII), and 0.5% N-methyliminodiacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[NH:20][CH2:19][C@@H:18]1[CH3:24])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.COC1C=C(C=CC=1)C(Cl)C1C=CC2C(=CC=CC=2)C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[NH:20][CH2:19][C@@H:18]1[CH3:24])[C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:16]=1
Reactant: COc1cccc(C(c2cccc3ccccc23)N2C[C@@H](C)NC[C@@H]2C)c1
Agent: COc1cccc(C(Cl)c2ccc3ccccc3c2)c1
Product: COc1cccc(C(c2ccc3ccccc3c2)N2C[C@@H](C)NC[C@@H]2C)c1

Procedure:
The compound 8 was prepared by following the synthesis procedure as described for compound 3, but substituting compound 2 for compound 7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23](=[O:24])[C:22]4[C:21](=[CH:28][C:27]([NH2:29])=[C:26]([Br:37])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)ccc4c3=O)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)c(Br)cc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a suspension of {1-[4-(7-amino-4-oxo-2-phenyl-4H-1-benzopyran-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (48 mg, 0.10 mmol) in chloroform (1.0 mL), was added N-bromosuccinimide (18 mg, 0.10 mmol) and the reaction mixture was stirred at RT for 1 hour. After this time, the mixture was poured into water and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, gradient 0 to 80% EtOAc in pentane) to yield the title compound as a yellow solid (34 mg, 61%). LCMS (Method B): RT=4.96 min, [M+H]+=561/563.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])[CH2:14][CH2:13]1)=[O:10])C.O[Li].O.Cl>C1COCC1.O.CCOC(C)=O>[Cl:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([Cl:29])[CH:25]=1)[CH2:21][O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[CH2:13][CH2:14]1)=[O:19]
Reactant: CCOC(=O)CCCCC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCCCC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3,5-dichlorobenzyl 4-(6-ethoxy-6-oxohexanamido)piperidine-1-carboxylate (step 1) (130 mg, 0.283 mmol) in THF (3 mL)/water (1 mL) was added LiOH.H2O (26.1 mg, 0.623 mmol) and the reaction mixture stirred at RT for 3 hrs. The resulting mixture was diluted with water and EtOAc and the aqueous portion acidified with 0.1 M HCl solution (pH 5-6). The resulting precipitate was collected by filtration and washed with water to afford the title product;
Reaction SMILES: [F:1][CH:2]([F:28])[C:3](=[S:27])[NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:26])[CH:13]=2)[CH2:7]1.[F:29]C(F)C(O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>>[F:28][CH:2]([F:1])[C:3](=[S:27])[NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:29])[C:15]([N:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:25])[CH2:22][CH2:23]3)=[C:14]([F:26])[CH:13]=2)[CH2:7]1
Reactant: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: O=C(O)C(F)F
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1

Procedure:
Following the procedure described in Example 6 for the preparation of 13 the amine 27 (prepared according to the procedure described in U.S. Pat. No. 6,342,523) is first condensed with difluoroacetic acid and the resulting amide is allowed to react with Lawesson's Reagent to give the title compound 26 which is purified by silica gel chromatography with 5% MeOH—CH2Cl2.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[C:16]([OH:18])=[O:17])=O)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Zn].Cl[Hg]Cl>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)c1ccncc1
Agent: Cl
Agent: Cl[Hg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C(O)[C@H]1CCCC[C@@H]1Cc1ccncc1
Reaction time: 0.25 h

Procedure:
A mixture of 8.5 M hydrochloric acid (10.5 mL), Zn (5.57 g, 85.2 mmol), and HgCl2 (0.557 g, 2.1 mmol) was stirred for 15 min, and then (1S, 2R)-2-(4-pyridylcarbonyl)cyclohexanecarboxylic acid (0.30 g, 1.3 mmol) was added. The reaction mixture was stirred at reflux for 20 h, and then diluted with 10% citric acid (75 mL), and then adjusted to pH=4 by addition of 10 M NaOH. The reaction mixture was extracted with ethyl acetate, washed with sat. brine, dried over MgSO4, filtered, and evaporated to give (1S, 2R)-2-(4-pyridylmethyl)-cyclohexanecarboxylic acid, as a white semi-solid (0.25 g, 90%).
Reaction SMILES: C(NC1N=C(S(C)=O)C(C(N)=O)=CN=1)(C)(C)C.Cl.N[C@H]1C[C@@H](O)C(C)(C)CC1.Cl.N[C@@H]1C[C@H](O)C(C)(C)CC1.CC(=O)OCC.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[C:57]([NH:61][C:62]1[N:67]=[C:66]([NH:68][C@@H:69]2[CH2:74][CH2:73][C:72]([CH3:76])([CH3:75])[C@H:71]([OH:77])[CH2:70]2)[C:65]([C:78]([NH2:80])=[O:79])=[CH:64][N:63]=1)([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C>[C:57]([NH:61][C:62]1[N:67]=[C:66]([NH:68][C@H:69]2[CH2:74][CH2:73][C:72]([CH3:75])([CH3:76])[C@@H:71]([OH:77])[CH2:70]2)[C:65]([C:78]([NH2:80])=[O:79])=[CH:64][N:63]=1)([CH3:58])([CH3:59])[CH3:60]
Reactant: CC(C)(C)Nc1ncc(C(N)=O)c(N[C@@H]2CCC(C)(C)[C@H](O)C2)n1
Agent: CC1(C)CC[C@@H](N)C[C@H]1O
Agent: CC1(C)CC[C@H](N)C[C@@H]1O
Agent: CS(=O)c1nc(NC(C)(C)C)ncc1C(N)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1ncc(C(N)=O)c(N[C@H]2CCC(C)(C)[C@@H](O)C2)n1
Temperature: 90 °C
Yield: 76 %

Procedure:
To a stirring suspension of 2-(tert-butylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (375 mg, 1.46 mmol) and a mixture of (1R,5R)-5-amino-2,2-dimethylcyclohexanol hydrochloride and (1S,5S)-5-amino-2,2-dimethylcyclohexanol hydrochloride (342 mg, 1.902 mmol) in DMF (4.877 mL) was added DI EA (0.767 mL, 4.39 mmol) and the reaction was heated to 90° C. overnight. The crude reaction mixture was concentrated under reduced pressure and then purified using reverse-phased semi-preparative HPLC (5-80% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure and redissolved in a mixture of ethyl acetate (125 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (75 mL). The combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was redissolved in a methanol (5 mL), passed over an Varian StratoSpheres HCO3 resin SPE tube for TFA removal (0.9 mmol bicarbonate equivalent), and then concentrated under reduced pressure to afford an oil that was triturated with diethyl ether and reconcentrated to give solids. The solids were dried for a few hours in a vacuum oven at 45° C. to afford a mixture of 2-(tert-butylamino)-4-((1R,3R)-3-hydroxy-4,4-dimethylcyclohexylamino)pyrimidine-5-carboxamide and 2-(tert-butylamino)-4-((1S,3S)-3-hydroxy-4,4-dimethylcyclohexylamino)pyrimidine-5-carboxamide (373 mg, 1.112 mmol, 76% yield).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH3:41][O:42]/[N:43]=[C:44](/[C:48]1[N:49]=[C:50]([NH:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:51][CH:52]=1)\[C:45](O)=[O:46].P(Cl)(Cl)(Cl)(Cl)Cl>CC#N.C(Cl)Cl.O>[Cl:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:45](=[O:46])/[C:44](=[N:43]\[O:42][CH3:41])/[C:48]3[N:49]=[C:50]([NH:53][C:54]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[S:51][CH:52]=3)[C:27](=[O:28])[N:4]2[C:5]=1[C:11]([O:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate prepared in Preparation No. 4 (2.29 g, 5.52 mmoles) in CH3CN (57 mL) was treated with bis(trimethylsilyl)acetamide (BSA, 4.09 mL, 16.6 mmoles) at room temperature for 50 minutes to give a clear solution. To the solution was added an acid chloride solution, which was prepared from (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IV-1) (2.04 g, 4.60 mmoles) and PCl5 (1.15 g, 5.52 mmoles) in methylene chloride (20 mL). The mixture was stirred at room temperature for 30 minutes, poured into cold water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with aqueous NaCl, dried and evaporated. The residual syrup (4 g) was chromatographed on a silica gel (150 g) column by eluting with 10:1 and 3:1 mixtures of toluene and ethyl acetate successively. The fractions containing the desired compound were combined and evaporated to afford 2.61 g (68%) of VI-1 as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.Cl.[C:22]1([N:28]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=3[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[CH:30]=[N:29][N:28]2[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Nc1cccc2c1cnn2-c1ccccc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and 1-phenyl-1H-indazol-4-amine hydrochloride (as the free base, Intermediate 8) except that ca. 5 drops of NMP were added to the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]1([CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[CH:11]=1)[OH:10].CS(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:9]2[CH:11]=[C:12]([OH:13])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Oc1cccc(Oc2ccc(Cl)cn2)c1
Temperature: 40 °C
Yield: 34.7 %

Procedure:
To a solution consisting of 5-chloro-2-fluoropyridine (1.3 mL, 13 mmol) and resorcinol (2.1 g, 19 mmol) and DMSO (30 mL) was added Cs2CO3 (6.3 g, 19 mmol). The reaction vessel was heated at 40° C. for 22 hours then diluted with CH2Cl2 (60 mL) and washed with saturated aq. NH4Cl (100 mL). The organic layer was dried (MgSO4) and concentrated. The crude residue was purified (FCC) to give the title compound (1.0 g, 37%). MS (ESI+): calcd. for C11H8ClNO2, 221.02. m/z found, 222.1 (M+H)+. 1H NMR (CDCl3): 8.14 (d, J=2.6 Hz, 1H), 7.65 (dd, J=8.7, 2.7 Hz, 1H), 7.26-7.22 (m, 1H), 6.89 (dd, J=8.7, 0.5 Hz, 1H), 6.69-6.65 (m, 2H), 6.60 (t, J=2.3 Hz, 1H).