Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][C@@H:22]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](S)C1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 160 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 937 mg, 2.77 mmol), (R)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (prepared in STEP C of Example 18, c.a. 3.60 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (80.1 mg, 0.138 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.1 mg, 0.0690 mmol) and N,N-diisopropylethylamine (725 microL, 4.15 mmol) in 1,4-dioxane (15 mL) was stirred at 160° C. for 1 h under microwave. The mixture was concentrated in vacuo and the residue was purified by amine gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (802 mg, 63% mmol) as a pale orange gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([OH:16])=O)[C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:22]3)=[O:16])[C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C1CCNC1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1cccc(Br)c1
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Yield: 94 %

Procedure:
In analogy to the procedure described in example 12D], 5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid and 3-(diethylamino)pyrrolidine gave the title compound in 94% yield as white needles. MS: 419.2 (MH+, 1 Br).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:46]([OH:48])=[O:47])[NH:17][C:18](=[O:45])[CH2:19][CH2:20][C@H:21]([C@@H:23]2[C@:40]3([CH3:41])[C@H:26]([C@H:27]4[C@H:37]([CH2:38][C@@H:39]3[OH:42])[C@:35]3([CH3:36])[C@@H:30]([CH2:31][C@H:32]([OH:43])[CH2:33][CH2:34]3)[CH2:29][C@H:28]4[OH:44])[CH2:25][CH2:24]2)[CH3:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:50]1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(CC)CC>CO>[CH3:50][O:47][C:46](=[O:48])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])[NH:17][C:18](=[O:45])[CH2:19][CH2:20][C@H:21]([C@@H:23]1[C@:40]2([CH3:41])[C@H:26]([C@H:27]3[C@H:37]([CH2:38][C@@H:39]2[OH:42])[C@:35]2([CH3:36])[C@@H:30]([CH2:31][C@H:32]([OH:43])[CH2:33][CH2:34]2)[CH2:29][C@H:28]3[OH:44])[CH2:25][CH2:24]1)[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@H](CCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 429.3 %

Procedure:
A solution of N6 -(phenylmethoxy)carbonyl-N2 -[(3α,5β,7α,12α)-3,7,12-trihydroxy-24-oxocholan-24-yl]-L-lysine 27.5 g) in MeOH (600 ml), kept at room temperature and under nitrogen atmosphere, was added to p-toluenesulfonic acid monohydrate (1.56 g; 8.2 mmol). After 20 h the reaction mixture was added to Et3N (0.832 g; 8.2 mmol). The mixture was evaporated under reduced pressure and the resulting crude was purified by flash chromatography to obtain the desired product (24.1 g; 35.2 mmol).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]=[N:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])[CH:12]=[CH2:13]>>[N:1]1([CH2:6][CH2:7][C:8]2[CH2:13][CH:12]([CH2:11][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[O:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCN1CCCC1=O
Reactant: ON=CCCN1CCCC1
Product: O=C1CCCN1CC1CC(CCN2CCCC2)=NO1
Yield: 19.8 %

Procedure:
The desired compound was prepared by the method of Example 8 from 400 mg (2.813 mmol) of 3-pyrrolidin-1-yl-propionaldehyde oxime prepared in Example 1 and 704 mg (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6, and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 7:1) as eluent to obtain 148 mg (20% yield) of 1-[3-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-isoxazol-5-yl-methyl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:3]=1[O:4]C1CCCCO1.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1>[OH:4][C:3]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:2]=1[B:26]([OH:27])[OH:25]
Reactant: COc1ccc(OC2CCCCO2)c(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(O)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
2-(2-Bromo-4-methoxyphenoxy)tetrahydropyran (1.9 g, 6.62 mmol) was dissolved in dry THF (25 ml) and the solution cooled to −78° C. under nitrogen. n-Butyl lithium (1.6M in hexanes, 4.6 ml, 7.36 mmol) was added dropwise with stirring over 10 minutes. The reaction was stirred at −78° C. for 1 hour. Triisopropoxy borane (1.6 ml, 6.9 mmol) was added dropwise and the mixture allowed to warm to room temperature overnight. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with DCM (2×200 ml). The combined organic extracts were washed with 2N hydrochloric acid (50 ml), dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane to give the title compound as a pale brown solid (660 mg, 59%); MS 166/167 (M-H)−; HPLC retention time (system 2) 3.53 minutes.
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][S:11][C:12]1[NH:17][C:16](=O)[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=1.CCOC1C=CC(N)=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:16]1[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=[C:12]([S:11][CH3:10])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Agent: CCOc1ccc(N)cc1
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)n2nccc2n1
Temperature: 25 °C
Yield: 81 %

Procedure:
N,N-Dimethylaniline (601 mg, 4.96 mmol) was added to a suspension of 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (1.88 g, 10.33 mmol) from 1c in POCl3 (29 mL). The reaction mixture was heated to reflux for 7 hours, and then cooled to room temperature, concentrated in vacuo, and diluted with cold water (110 mL). The resulting solid was collected by vacuum filtration, washed with cold water and hexane, and then air dried to give 1.68 g (81%) of 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[C:8]([O:12][C:13](=[O:16])[CH2:14]Br)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH:6]([C:2]1[N:1]([CH2:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:16])[CH:5]=[CH:4][N:3]=1)=[O:7]
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccnc1C=O
Temperature: 110 °C
Yield: 39 %

Procedure:
To a solution of 2-imidazole carboxaldehyde (1.00 g, 10.4 mmol) in DMF (1 mL) was added 1 eq. tert-butylbromoacetate, potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (850 mg, 4.03 mmol, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.6 (s, H), 7.23 (s, H), 5.15 (s, 2H), 1.40 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCC(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 57.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (170 mg, 0.629 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine (150 mg, 0.572 mmol) and diisopropylethylamine (0.199 ml, 1.14 mmol) in dimethylsulfoxide (2.0 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (127 mg, 58.0%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9](Cl)=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].C(Cl)Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH2:21]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH:21][C:9]([C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:8][S:7][CH:6]=1)=[O:10]
Reactant: CCOc1cscc1C(=O)Cl
Reactant: Nc1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cscc1C(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8.8 g. portion of 4-ethoxy-3-thiophenecarbonyl chloride is dissolved in 100 ml. of methylene chloride and added dropwise to a mixture of 6.6 g. of 5-chloro-2-hydroxyaniline in 100 ml. of methylene chloride and 6.5 ml. of triethylamine. This mixture is stirred at ambient temperature overnight, concentrated to 100 ml. and filtered. The filtrate is allowed to stand overnight and the precipitate which forms is collected, washed with water and dried in vacuo. This combined precipitate is recrystallized from 200 ml. of ethanol, treated with charcoal, filtered through diatomaceous earth and concentrated giving 5'-chloro-4-ethoxy-2'-hydroxy-3-thiophenecarboxanilide as red brown crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH:27]1([NH2:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:37][CH:27]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][CH2:28]2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: NC1CCCc2ccccc21
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(NC3CCCc4ccccc43)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=466.1 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonyl chloride and rac-1,2,3,4-tetrahydro-1-naphthylamine.
Reaction SMILES: [Br-].[CH3:2]C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)/C=C/C.O1[CH2:30][CH2:29][CH2:28][CH2:27]1.C([Li])CCC.[CH3:36]/[C:37](=[CH:40]\[C:41](\[CH3:44])=[CH:42]\[CH3:43])/[CH:38]=O>CCCCCC.O>[CH3:27][C:28]([CH:36]=[C:37]([CH3:38])[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][CH3:2])=[CH:29][CH3:30]
Reactant: C1CCOC1
Reactant: C/C=C/C(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C/C=C(C)/C=C(\C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CC=CC(C)=CC(C)=CC(C)=CC
Temperature: 25 °C

Procedure:
(1-Methyl-2(E)-butenyl)triphenylphosphonium bromide from Example 9 (0.62 g, 0.0015 mole) was added to a dry flask with 5 ml tetrahydrofuran. The flask was equipped with magnetic stirrer and septum; the reaction was carried out under nitrogen. The salt did not dissolve completely but became a sticky suspension. The mixture was cooled over ice, and butyllithium (2.5 M in hexane) was added dropwise, with stirring, until the color change became permanent; then an additional 0.0015 mole was added. The solid in the flask dissolved as it was converted to the ylide. One hundred milligrams of (2E,4E)-2,4-dimethyl-2,4hexadienal (0.0008 mole), compound 15, a previously known compound (Patel and Pattenden, 1985), was added to the Wittig reagent, and the mixture was allowed to warm to room temperature. The mixture was stirred for 2 hr, and it was again cooled over ice. Water was added dropwise until the red color of the solution had disappeared, and ca. 2 ml more water was added. The mixture was diluted with hexane and the organic layer dried over sodium sulfate. The solvent was removed and the product passed through a silica column with hexane. By capillary GC the product was 61% the (E,E,E,E) isomer, ca. 31% the (E,E,Z,E) isomer, and ca. 8% by-products, after clean-up on silica. Further purification on the AgNO3HPLC column yielded the (E,E,E,E) isomer in >97% purity.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[OH:13].C(N(CC)CC)C.[CH2:21]=[O:22].Cl>C(#N)C.C(OCC)C>[OH:4][C:5]1[C:6]([OH:13])=[C:7]([CH2:11][CH3:12])[CH:8]=[CH:9][C:10]=1[CH:21]=[O:22]
Reactant: CCc1cccc(O)c1O
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccc(C=O)c(O)c1O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Magnesium chloride (1.71 g, 18 mmol) was added at room temperature to a solution of 10 (1 g, 7.2 mmol) in acetonitrile (10 mL), followed by triethylamine (6.3 mL, 45 mmol). Paraformaldehyde (1.47 g, 49 mmol) was then added portionwise to the stirred suspension and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature then poured into a vigorously stirred mixture of 50 mL of 5% HCl and 50 mL of diethyl ether. The organic phase was separated, and the aqueous layer re-extracted with 50 mL of ether. The combined organic extracts were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (cyclohexane:AcOEt 6:1) to give 0.9 g of 11:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1COCC1.O.[OH-].[Li+].Cl>CO.O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-5a, 79.58 mmol, 17.05 g) was taken up in 300 mL 2:1 THF:H2O in 500 mL round-bottom flask. To this solution was added lithium hydroxide monohydrate (120 mmol, 5.01 g). To this was added 100 mL MeOH. The reaction was allowed to stir overnight at room temperature. The reaction mixture was acidified to pH=3 with 1N HCl(aq) and extracted with 100 mL DCM (x5). The combined organics were then dried over Na2SO4 and the solvents were removed in vacuo to yield 1,4-dioxaspiro[4.5]decane-8-carboxylic acid (Int-5b) (14.96 g, 100% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][C@H:34]([OH:36])[CH3:35].[OH-].[Na+:38]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([O-:23])=[C:7]([C:24]([NH:32][CH2:33][C@H:34]([OH:36])[CH3:35])=[O:25])[C:6]1=[O:29].[Na+:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: C[C@@H](O)CN
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](O)CNC(=O)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The resulting material was treated with 1.3 equivalents of 1N NaOH solution and triturated with CH3CN to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.59 (1H, br), 8.14 (1H, s), 7.26 (3H, m), 7.10 (2H, m), 4.92 (2H, s), 4.80 (1H, br), 3.99 (2H, s), 3.67 (1H, br), 3.15 (2H, m), 3.08 (3H, s), 2.78 (3H, s), 1.04 (3H, br d, J˜5 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1882.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl-].[NH4+]>CCO.O.ClCCl.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH:4]([CH:2]3[CH2:3][CH2:1]3)[C:9](=[O:10])[NH:8][C:7]=2[CH:11]=1
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2OC1C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)NC(=O)C(C1CC1)O2
Temperature: 90 °C

Procedure:
To a solution of 200 mg of 2-(2-cyclopropyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine (1 g) in EtOH/water (20 mL; 2:1 v/v) was added 5 eq of iron and 5 eq of ammonium chloride and the reaction was heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered. The layers were separated, the aqueous was extracted once with dichloromethane, the combined organics layers were dried over magnesium sulfate, the solution filtered and the filtrate evaporated in vacuo to give the desired product 6-amino-2-(2-cycloproply)-3-oxo-4H-benz[1,4]. MS (m/e): 191 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[OH-].[NH4+:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1ccc(Br)cc1S(N)(=O)=O
Yield: 55 %

Procedure:
Prepared by general procedure III from 5-Bromo-2-methyl-benzenesulfonyl chloride (1.89 g, 7 mmol) and ammonium hydroxide (20 mL) to give the title compound (0.96 g, 55%) as a white solid. MS (ISN) 248.0[(M−H)−], 250.0[(M+2−H)−].
Reaction SMILES: Cl.[N:2]1([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(O)C>ClCCl>[C:24]([N:13]1[CH2:14][CH2:15][CH2:16][N:10]([C:8]([N:2]2[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)=[O:9])[CH2:11][CH2:12]1)(=[O:26])[CH3:25]
Reactant: O=C(N1CCCNCC1)N1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of 1-(4-morpholinecarbonyl)-1,4-diazepane hydrochloride (50 g, 0.2 mol) and triethylamine (42 ml, 30.5 g, 0.3 mol) in dichloromethane (400 ml) at 5° C. was added acetic anhydride (23 ml, 24.9 g, 0.24 mol) dropwise over 15 minutes and the reaction was then stirred for a further 2 hours at room temperature under nitrogen. Dilution with dichloromethane (600 ml) was followed by washing with saturated aqueous sodium bicarbonate (2×200 ml) and the combined aqueous layers extracted with dichloromethane (1×100 ml). The dichloromethane layers were combined and washed with saturated brine, dried over MgSO4 and evaporated to give a light brown oil. This was dissolved in dichloromethane (300 ml) and treated with triethylamine (8 ml, 5.8 g, 0.06 mol) and ethanol (5 ml), stirred for 1 hour at room temperature then washed with saturated sodium bicarbonate and the aqueous layer extracted with dichloromethane (5×). The combined dichloromethane layers were dried over MgSO4 and evaporated under reduced pressure to give a yellow oil which was then azeotroped with dichloromethane (4×) to give the title compound as a yellow oil (47.1 g, 92%). Rf 0.45 (0.880 aqueous ammonia: methanol:dichloromethane 1:10:90, v/v). MS m/z 256 (MH)+. Found: C,52.62; H,8.18; N,15.02; C12H21N3O3 0.3CH2Cl2 requires C, 52.61; H, 7.75; N,14.96%.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:6])#[N:2].BrC1C=CC(S)=CC=1.CO.I([O-])(=O)(=O)=[O:33].[Na+]>O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)=[O:33])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(Br)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Sc1ccc(Br)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-N-Cyanomethyl-2-(4-bromophenylsulfanylmethyl)cyclohexanecarboxamide (197 mg, 0.536 mmol), prepared as in Example 1 but substituting 4-fluorothiophenol with 4-bromothiophenol, was weighed into a 50 mL round bottom flask fitted with a stirrer and vented cap. Methanol (20 mL) was added to the flask and the reaction mixture was warmed to 50° C. until a clear colorless solution formed. Added sodium periodate (128 mg, 0.599 mmol) solution in water (2.0 mL). A white precipitate slowly formed. The reaction mixture was stirred at 50° C. for 8 h and then concentrated on a rotary evaporator. The residue was triturated in hot water (20 mL) and the reaction mixture was cooled to room temperature. Solids were isolated by filtration, washed thoroughly with water and dried under high vacuum to give trans-N-cyanomethyl-2-(4-bromophenylsulfinylmethyl)cyclohexanecarboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([O:18]C)=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:14][CH2:15]2)[C@H:11]([C:16]([OH:18])=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](C2CC2)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 2.66 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylate in 60 ml of methanol is added dropwise a solution of 255 mg of lithium hydroxide in 30 ml of water under ice-cooling. The reaction mixture is warmed to room temperature, stirred for one hour and evaporated under reduced pressure to remove methanol. Chloroform is added to the residue. The pH of the mixture is adjusted to about pH 2 with 10% hydrochloric acid under ice-cooling thereto. The chloroform layer is washed with brine, dried, and evaporated under reduced pressure to remove the solvent to give 2.65 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylic acid.