Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[C:26](F)[C:25]([CH3:29])=[CH:24][C:23]=1[N+:30]([O-:32])=[O:31]>>[Cl:21][C:22]1[C:23]([N+:30]([O-:32])=[O:31])=[CH:24][C:25]([CH3:29])=[C:26]([CH:27]=1)[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Product: COc1ccc(Cn2nc(C)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Yield: 75.3 %

Procedure:
Prepared from 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in Example 5, Step B) and 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0.106 g, 0.557 mmol), according to the procedure of Example 13, Step A. Purified by Biotage 40S column eluting with 3:1 hexane/EtOAc then EtOAc to obtain the product (184 mg, 75%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.36 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.21 (s, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.23 (d, J=5.1 Hz, 1H), 5.58 (s, 1H), 3.77 (s, 3H), 2.63 (s, 3H), 2.31 (s, 3H). LRMS (APCI pos) m/e 439 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(F)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure A by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4-fluorophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in tetrahydrofuran. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.93-2.05 (m, 4H), 2.97-3.07 (m, 2H), 4.05-4.15 (m, 2H), 4.99-5.02 (m, 1H), 7.23-7.41 (m, 4H), 8.22 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=414.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13]>CO.[C].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:14]=1
Reactant: COCCCCNc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCCCCNc1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.2 %

Procedure:
5-Fluoro-N-(4-methoxybutyl)-2-nitroaniline (494 mg) was dissolved in methanol (20 ml), 10% palladium carbon (50% in water, 100 mg) was added, and the mixture was stirred under a hydrogen stream at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (451 mg) as an oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30]>>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)CC1
Reactant: NO
Agent: Cl
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)CC1

Procedure:
The title compound is prepared from 4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-piperidine-1-carbonitrile and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 5): tR=0.54 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].[CH3:16][CH2:17]O>C(Cl)Cl>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCO
Reactant: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1O
Yield: 70 %

Procedure:
H2SO4 (1.5 mL, 28.14 mmol) was added to a solution of salicylic acid (1.50 g, 10.860 mmol) in EtOH (50 mL). The reaction mixture was refluxed for 2 days, allowed to reach r.t., and it was diluted with CH2Cl2 (200 mL). The organic layer was washed with Na2CO3 (1 M aqueous solution, 200 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated to furnish 1.26 g of ethyl 2-hydroxybenzoate (yellow-coloured oil, yield: 70%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:4][C:3]1=S.[OH:12]O>[OH-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:4][C:3]1=[O:12]
Reactant: Cn1c(C(F)(F)F)n[nH]c1=S
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(C(F)(F)F)n[nH]c1=O
Reaction time: 2 h
Yield: 67.6 %

Procedure:
18.3 g (0.1 mol) of 4-methyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazole-3-thione are introduced into 100 ml of 2.5-molar sodium hydroxide solution. A hydrogen peroxide solution (34 ml of 30% strength hydrogen peroxide: 0.33 mol of H2O2) is slowly added dropwise at 40° C. to 50° C. and stirring of the mixture is continued for 2 hours at 50° C. Excess oxidant is then removed using sodium bisulphite, and the mixture is subsequently acidified using concentrated hydrochloric acid. The reaction mixture is then refluxed for 15 hours, subsequently stirred into ice-water and then extracted using methylene chloride. The extraction solution is dried using sodium sulphate and filtered. The solvent is carefully removed from the filtrate by distillation under a water pump vacuum. 11.3 g (68% of theory) of 4-methyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as a solid residue of melting point 64° C.
Reaction SMILES: [CH:1]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>C(O)C.C1COCC1>[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][C:1]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(CBr)c1OC
Reactant: CCOC(=O)C1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1(Cc2cccc(OC)c2OC)CCCCCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of ethyl cycloheptane carboxylate (14 g, 82.4 mmol, prepared by esterification of the acid, which was obtained from Aldrich, by refluxing in ethanol in the presence of an acid catalyst), in 600 mL anhydrous THF cooled to -78° C. was added 60 mL of 1.5M LDA (monotetrahydrofuran in hexane, Aldrich) via syringe. The resulting light yellow reaction solution was stirred at -78° C. for 45 min and the benzyl bromide (from step A above) was added (19 g dissolved in 75 mL of THF, 82.4 mmol). The reaction was stirred at -78° C. for 4 hours, then it was quenched by addition of sat'd. NH4Cl, water and ether. The layers were separated, and the organic layer was washed with 1M HCl, water, and brine. The organic layer was dried over MgSO4, filtered, and evaporated to yield a light amber oil (28 g) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])[NH:8][C:9](=[O:15])[CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:29][C@H:30]([C:34](O)=[O:35])[CH:31]([CH3:33])[CH3:32])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([O:5][C:6](=[O:21])[CH:7]([CH:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])[N:8]([C:34](=[O:35])[C@H:30]([CH:31]([CH3:32])[CH3:33])[NH:29][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:9](=[O:15])[CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(O)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](N)C(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCC(O)C(=O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C(=O)OC(C)(C)C)C(N)C(C)C
Reaction time: 2 h

Procedure:
The ester compound thus formed was admixed with 155.9 mg (0.718 mmol) of Boc-L-valine, 176.1 mg (1.303 mmol) of N-hydroxyl-benzotriazole and 3.5 ml of dichloromethane. The resulting reaction mixture was cooled with ice, admixed with 499.4 mg (2.605 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, stirred for 2 hours, and further stirred at room temperature for 16.5 hours. The reaction mixture was diluted with 7 ml of dichloromethane, successively washed with 6 ml of a 1% aqueous citric acid solution, 6 ml of water, 6 ml of a saturated aqueous sodium hydrogen carbonate solution and 6 ml of water, dried over anhydrous sodium sulfate, and distilled to remove the solvent therefrom so that crude Boc-L-valyl-(2RS, 3RS)-3-amino-2 hydroxypentanoyl-D-leucine t-butyl ester was obtained as an amorphous material. The crude product was used in the next reaction step without a purification operation.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:13]([NH:14][C:15](=[O:31])/[C:16](/[C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:17]\[O:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH3:21])[C:12](=[O:32])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].C([BH3-])#N.[Na+].[CH:37](=O)[CH3:38]>C([O-])(=O)C.[Na+].O>[NH2:30][C:27]1[S:28][CH:29]=[C:25](/[C:16](=[N:17]/[O:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH3:21])/[C:15]([NH:14][CH:13]2[C:12](=[O:32])[N:7]3[C:8]([C:9]([OH:11])=[O:10])=[C:3]([CH2:2][NH:1][CH2:37][CH3:38])[CH2:4][S:5][C@H:6]23)=[O:31])[N:26]=1
Reactant: CCC(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reactant: CC=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCNCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(CC)C(=O)O)c3csc(N)n3)[C@H]2SC1

Procedure:
The cephalosporin starting material may be prepared as follows: To a stirred solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]ceph-3-em-4-carboxylic acid (more polar isomer, 2.6g) in 2.5% (w/v) pH 5.5 sodium acetate buffer (50 ml) was added sodium cyanoborohydride (0.34 g), followed by acetaldehyde (0.3 ml) in water (5 ml) over 40 minutes. The reaction mixture was then concentrated, diluted to 50 ml with water, and the pH adjusted to 3.5 with HOAc. Careful chromatography on Diaion HP20SS, eluting with H2O/CH3CN, (92.5:7.5) gave 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]-3-ethylaminomethylceph-3-em-4-carboxylic acid, having the following n.m.r. spectrum in solvent A: 0.96 (t, 3H); 1.18 (t, 3H); 1.81 (quintet, 2H); 2.94 (q, 2H); 3.38 (d, 1H); 3.42 (d, 1H); 3.61 (d, 1H); 3.78 (d, 1H), 4.46 (t, 1H); 5.03 (d, 1H); 5.76 (d, 1H); 6.88 (s, 1H). Retention time 4.2 minutes on a reversed phase Partisil PXS 10/25 ODS-2 column, using MeOH/H2O/HOAc,,30:70:1, v/v/v, as eluant.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:35]=[CH:34][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][S:28]([CH:31]5[CH2:33][CH2:32]5)(=[O:30])=[O:29])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:17]1[CH:18]=[C:13]([N:10]2[C:9]3[CH:34]=[CH:35][C:6]([C:4]4[CH:5]=[N:1][N:2]([S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=4)=[CH:7][C:8]=3[N:12]=[CH:11]2)[CH:14]=[C:15]([NH:27][S:28]([CH:31]2[CH2:32][CH2:33]2)(=[O:29])=[O:30])[CH:16]=1
Reactant: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1)C1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)n1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)cn1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of the compound of Example 203 (50 mg, 0.101 mmol) in DCM was added pyridine (16 mg, 0.202 mmol, 2.0 eq.) followed by methanesulfonyl chloride (14 mg, 0.122 mmol, 1.2 eq.). The mixture was stirred for 1 h and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 60% yield (40 mg). H-NMR (400 MHz, DMSO-D6) δ=10.32 (s, 1H), 8.95 (s, 1H), 8.90 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 7.88 (d, 1H), 7.76 (dd, 2H), 7.63 (d, 2H), 7.52 (s, 1H), 7.50-7.47 (m, 1H), 7.30-7.29 (dt, 1H), 3.61 (s, 3H), 2.90-2.86 (m, 1H), 1.04-1.02 (d, 4H); LC-MS (ESI): Calculated mass: 569.6; Observed mass: 569.9 [M+H]+ (rt: 0.64 min).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([C@H:10]3[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][O:8]2)=[N:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([CH:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][OH:8])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C2(c3ncc(Br)s3)CO2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](C(CO)c2ncc(Br)s2)CC1

Procedure:
A solution in DCM (0.7 mL) of ethyl trans-4-[2-(5-bromo-1,3-thiazol-2-yl)oxiran-2-yl]cyclohexanecarboxylate (30 mg, 0.082 mmol) from Step 2 was treated with trifluoroacetic acid (0.266 mL, 1.665 mmol) and triethylsilane (0.128 mL, 1.665 mmol) and left at 45° C. 16 h. The volatiles were removed under reduced pressure and the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2-hydroxyethyl]cyclohexanecarboxylate which was used as such without further characterization. MS ESI calc'd. for C14H20BrNO3S [M+H]+ 362, 364, found 362, 364.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([O:29]CC)=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CCO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([OH:29])=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCN1CCc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was washed with AcOEt (20 ml). The aqueous layer was adjusted to pH 1-2 with hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([C:19]([O:21]CC)=[O:20])[C:6]=1[C:24]([O:26]CC)=[O:25])[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([C:19]([OH:21])=[O:20])[C:6]=1[C:24]([OH:26])=[O:25])[CH2:2][CH3:3]
Reactant: CCCOc1c(C(=O)OCC)c(C(=O)OCC)c(OCCC)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1c(C(=O)O)c(C(=O)O)c(OCCC)c2ccccc12
Temperature: 60 °C
Yield: 90.8 %

Procedure:
Diethyl 1,4-bis(propyloxy)-2,3-naphthalenedicarboxylate (11.45 g, 29.5 mmol) was dissolved in ethanol (70 ml) and treated with sodium hydroxide (3.54 g, 88.5 mmol) dissolved in water (15 ml). This was heated at 60° C. under argon for 4 hours. The reaction was confirmed to be complete by LC/MS and thin layer chromatography. The reaction mixture was cooled to room temperature and evaporated to a third of the volume. This was acidified to pH2 with hydrochloric acid (2N) and extracted with ethyl acetate (3×100 ml). Combined organics washed with water, brine and dried over magnesium sulphate. Solvent was evaporated to give the title compound as a yellow solid (8.91 g, 26.8 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].[NH:25]1CCNCC1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][NH:25][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Reactant: C1CNCCN1
Solvent: CCO
Product: CCOC(=O)c1c(N2CCNCC2)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30) and 1.72 g. (0.02 mole) of piperazine in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was diluted with 100 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated in an evaporating dish at room temperature. The residue was recrystallized from heptane to give 0.3 g. of product, m.p. 137°-139° C.
Reaction SMILES: C(O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C2(C3OCCO3)OC2)C1)(=O)C.C([O:35][C@H:36]1[C@@H:62]2[O:63][C@@H:61]2[C@@:60]2([CH3:64])[C:38](=[CH:39][CH:40]=[C:41]3[C@@H:59]2[CH2:58][CH2:57][C@@:56]2([CH3:65])[C@H:42]3[CH2:43][CH2:44][C@@H:45]2[CH:46]([CH:48]2[O:53][CH2:52]C(C)(C)[CH2:50][O:49]2)[CH3:47])[CH2:37]1)(=O)C>>[O:53]1[CH2:52][CH2:50][O:49][CH:48]1[CH:46]([C@@H:45]1[C@:56]2([CH3:65])[C@H:42]([C:41]3[C@H:59]([CH2:58][CH2:57]2)[C@:60]2([CH3:64])[C:38]([CH2:37][C@@H:36]([OH:35])[C@@H:62]4[O:63][C@@H:61]42)=[CH:39][CH:40]=3)[CH2:43][CH2:44]1)[CH3:47]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H](C5(C6OCCO6)CO5)[C@@]4(C)CC[C@@H]32)C1
Product: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.1 %

Procedure:
The procedure of Example 23 was repeated except that 4.5 mg (0.0106 mmole) of 20-(1,3-dioxolan-2-yl)--epoxypregna-5,7-dien-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 3.7 mg of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol (yield: 90%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[Br-].[Na+]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: BrCCCCBr
Reactant: CC(C)CCOCCCCO
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOCCCCOCCCCBr
Reaction time: 0.5 h

Procedure:
1.77 g (0.041 mol) of 55% sodium hydride dispersion in oil are carefully added over the course of 40 minutes, under nitrogen and while stirring, to 26.0 g (0.163 mol) of 4-isopentyloxy-butanol. The mixture is stirred at 60° for 30 minutes and 11.4 g (0.053 mol) of 1,4-dibromobutane are subsequently added dropwise and it is stirred at 60° for 20 hours. The resulting sodium bromide is suction filtered, washed with ether and the filtrate is evaporated. The residue is fractionally distilled in a high vacuum and apart from the excess 4-isopentyloxy butanol, 1-bromo-4-(4-isopentyloxy-butyloxy)-butane, having a B.P. of 121-123°/0.7 mm Hg, is obtained as a colourless liquid.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]3([C:15]4[C:20]([C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=4)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3.N1CCC[C@H]1C(O)=O.[CH3:30][S:31]([O-:33])=[O:32].[Na+].[OH-].[Na+]>CS(C)=O.[Cu]I>[CH3:30][S:31]([C:2]1[C:7]2[O:8][C:9]3([C:15]4[C:20]([C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=4)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)(=[O:33])=[O:32]
Reactant: Nc1ncc2c(n1)C1(CCCCC1)Oc1c(Br)cccc1-2
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cccc2c1OC1(CCCCC1)c1nc(N)ncc1-2
Temperature: 100 °C
Yield: 12.1 %

Procedure:
Copper (I) iodide (28 mg, 0.15 mmol, 0.4 eq) was added to a degassed solution of 7-bromospiro[chromeno[3,4-d]pyrimidine-5,1′-cyclohexan]-3-amine (44) (0.126 g, 0.36 mmol), (S)-pyrrolidine-2-carboxylic acid (0.034 g, 0.29 mmol), sodium methanesulfinate (0.074 g, 0.73 mmol) and sodium hydroxide (0.015 g, 0.36 mmol) in DMSO (1 mL) under Argon. The mixture was heated at 100° C., for 4 days. After workup, chromatography on silica gel afforded 15 mg of 7-(methylsulfonyl)spiro[chromeno[3,4-d]pyrimidine-5,1′-cyclohexan]-3-amine (45) as a brown solid. LCMS-ESI (POS), M/Z, M+1: Found 345.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([C:15]([O:17][CH3:18])=[O:16])=[N:7][C:6]=1[C:19]([O:21][CH3:22])=[O:20])=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH:6]([C:19]([O:21][CH3:22])=[O:20])[NH:7][CH:8]([C:15]([O:17][CH3:18])=[O:16])[CH:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10]1)=[O:4]
Reactant: COC(=O)c1nc(C(=O)OC)c(C(=O)OC)nc1C(=O)OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1NC(C(=O)OC)C(C(=O)OC)NC1C(=O)OC

Procedure:
A solution of tetrakis-methoxycarbonylpyrazine (5.3 g, 16.9 mmol) (prepared in accordance with J. Org. Chem. 37 (19), p 2963 (1972)) in 800 ml of dry ethanol, was hydrogenated at 50 bar in the presence of 10 g 5% palladium on charcoal at 80° C. for 16 hours. After cooling, the solution was filtered and evaporated to give slightly yellow crystals:
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:24])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (4-trifluoromethyl-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 381 (M+H)+.