Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])CCC.[CH:24](OCC)=[O:25].C(OCC)(=O)C>CCOCC>[CH2:1]([O:3][P:4]([C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([CH:24]=[O:25])=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC=O
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 22.4 %

Procedure:
To a solution of [Difluoro-(4-iodo-phenyl)-methyl]-phosphonic acid diethyl ester (1.6 g, 4.1 mmol) in anhydrous ether (40 mL) at -78° C. was added dropwise n-butyl lithium (2.5 M in hexanes, 2.5 mL, 6.1 mmol). The brown solution was stirred at -78° C. for 2 minutes. Ethyl formate (0.66 mL, 8.2 mmol) was then added, and the reaction was stirred for 10 minutes at -78° C. The mixture was then quenched with saturated ammonium chloride (10 mL) and warmed to room temperature. The reaction was then diluted with ether. The organic layers were washed with saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a yellow oil. Chromatography of the residue [3:7, ethyl acetate:hexanes] gradient to (1:1)] afforded the aldehyde (268 mg, 22%) as a clear oil. 1H NMR (400 MHz, DMSO): δ 10.28 (s, 1H), 8.25 (d, 2H), 7.97 (d, 2H), 4.42 (m, 4H), 1.40 (t, 6H).
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH:28]=O.C(O)(=O)C>C(O)C>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:28][C:27]2[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C=C2CC3C4CCc5cc(O)ccc5C4CCC3(C)C2=O)cc(OC)c1OC
Reaction time: 4 h

Procedure:
Potassium hydroxide (1.0 g) was added to a solution of estrone (1.350 g, 2.0 mmol) and 3,4,5-trimethoxybenzaldehyde (1.00 g, 5.10 mmol) in ethanol (50 ml) at room temperature. The resulting dark brown solution was stirred at this temperature for 4 h, then glacial acetic acid (ca. 2.5 ml) was added with stirring. The colour changed to yellow and a white solid precipitated. The solid was filtered off and washed with water (50 ml), ethanol (20 ml), diethyl ether (50 ml) and hexane and recrystallised from ethanol. Yield: 2.063 g (92%) light yellow crystals. 1H-NMR (CDCl3, 400 MHz), δ: 1.00 (s, 3H), 1.40-1.78 (m, 5H), 2.00-2.11 (m, 2H), 2.26-2.34 (m, 1H), 2.38-2.56 (m, 2H), 2.84-3.04 (m, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 4.93 (s, 1H, —OH), 6.60 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 6.80 (s, 2H), 7.17 (d, J=8.2 Hz, 1H), 7.40 (s, 1H). 13C-NMR (CDCl3, 100 MHz), δ: 15.0, 26.4, 27.2, 29.4, 32.1, 38.4, 44.4, 48.2, 49.0, 56.6, 61.3, 108.2, 113.2, 115.6, 126.6, 131.3, 131.9, 133.9, 135.2, 137.9, 139.7, 153.4, 154.0, 209.9. LRMS (FAB+): 449.3 (100, [M+H]+). LRMS (FAB−): 447.3 (100, [M−H]−). HRMS (FAB+): 448.223763.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>ClCCl>[CH3:1][C@@H:2]1[N:7]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 90.9 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-methyl-1-piperazinecarboxylate (500 mg, 2.497 mmol) in dichloromethane (20 ml) was added DIPEA (0.654 ml, 3.74 mmol) and then portionwise addition of 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.445 ml, 2.62 mmol) at room temperature and the resultant mixture stirred under an atmosphere of argon for 16 hours. The reaction was worked up by the addition of 1M HCl solution (75 mL) and dichloromethane (75 mL), the layers were separated and the organic layer was then washed with 2M NaOH solution (75 mL). The organic phase was separated, dried (MgSO4) and concentrated to dryness to give 1,1-dimethylethyl(3S)-3-methyl-4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate (963 mg, 2.269 mmol). This was dissolved in 1,4-dioxane (4 mL), HCl (4M in 1,4-Dioxane) (2.269 mL, 9.08 mmol) was added and the resultant mixture stirred under an atmosphere of argon for 2 h. After this time a white precipitate had formed so methanol (5 ml) was added to solubilize the precipitate and the reaction stirred for a further 30 min. The reaction was concentrated to dryness giving a white solid which was triturated with Et2O and the solid isolated by filtration under vacuum to give the title compound (585 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[NH:13][C:12]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][N:44]1[CH:48]=[N:47][C:46]([CH2:49]O)=[N:45]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([O:23][CH2:49][C:46]3[N:47]=[CH:48][N:44]([CH3:43])[N:45]=3)=[N:13][C:12]=12
Reactant: Cn1cnc(CO)n1
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cnc(COc2nc3c(-c4ccccc4F)nnn3cc2-c2ccccc2)n1
Yield: 48.8 %

Procedure:
3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (77 mg, 0.25 mmol), triphenylphosphine (165 mg, 0.63 mmol) and (1-methyl-1H-1,2,4-triazol-3-yl)methanol (80 mg, 0.63 mmol) were suspended in dry tetrahydrofuran (1.5 ml). Diethyl azodicarboxylate (100 μl, 0.63 mmol) was added and a solution resulted immediately. The reaction was stirred at room temperature for 48 hours before purification by preparative tlc (40% EtOAc/hexanes) to give a white solid which was recrystallised from ethyl acetate/hexanes to afford 3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[1,5-α]pyrimidine (49 mg, 49%) as white needles, m.p. 170-171° C.; δH (400 MHz, d6-DMSO) 3.84 (3H, s, NCH3), 5.57 (2H, s, OCH2), 7.35-7.41 (2H, m, ArH), 7.43-7.51 (4H, m, ArH), 7.73 (2H, dd, J=8.1 and 1.8 Hz, ArH), 8.14 (1H, td, J=7.5 and 1.8 Hz, ArH), 8.45 (1H, s, triazole CH), 9.51 (1H, s, pyrimidine CH); m/z (ES+) 402 (M+H+).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH3:42])=[C:36]([CH:39]=1)[CH:37]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:37][C:36]2[CH:39]=[C:32]([Br:31])[CH:33]=[CH:34][C:35]=2[O:40][CH2:41][CH3:42])[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: CCOc1ccc(Br)cc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(Br)cc1CN1CCC(CNC(=O)CNC(=O)c2cc(F)c(F)cc2N)CC1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-bromo-2-ethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.030 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. for 13 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×3). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material were added dichloromethane (1 mL) and trifluoroacetic acid (TFA) (0.50 mL) and the solution was stirred at room temperature for 10 min. The reaction mixture was concentrated, and the residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. Preparative TLC (SiO2, ethyl acetate/methanol=10/1) gave 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compound No. 2052) (10.2 mg, 38%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 539.2 (M++H, C24H29BrF2N4O3).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:17][C@H:16]([C:18]([O:20]C)=O)[O:15][C:14]3=[O:22])=[CH:12][C:7]=2[S:6][C:5]1=[O:23])([CH3:3])[CH3:2].[CH3:24][NH2:25]>CO>[CH3:24][NH:25][C:18]([C@@H:16]1[O:15][C:14](=[O:22])[N:13]([C:11]2[CH:10]=[CH:9][C:8]3[N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:23])[S:6][C:7]=3[CH:12]=2)[CH2:17]1)=[O:20]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C(C)C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The methyl(5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo -5-oxazolidinecarboxylate (EXAMPLE 31, Step 3, 2.89 g, 8.59 mmol) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at ambient temperature for 45 mins and then filtered to give the title compound, mp 172-173.5° C.; MS (ESI+) for C15H17N3O4S m/z 336 (M+H)+; [α]25D−43 (c 0.98, DMSO).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH3:15]>CO>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH2:15])=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: N
Solvent: CO
Product: Nc1ncc(-c2ccc(F)cc2)cn1

Procedure:
2-Chloro-5-(4-fluorophenyl)pyrimidine (376 mg) in 7M of ammonia in methanol (10 mL) in a sealed tube was heated at 50° C. overnight. After concentration, the product was obtained (360 g) which was used in the next reaction step without further purification. LCMS: (M+H)=190.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]([F:39])([F:38])[C:27]1[C:35]2[CH:34]=[C:33]([CH:36]=O)[S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]2[S:32][C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:38])([F:25])[F:39])[C:35]=3[CH:34]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cc2c(C(F)(F)F)cccc2s1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1cccc2sc(CNc3cccc(-c4c(-c5ccccc5)nnc5c(Cl)cccc45)c3)cc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 4-trifluoromethyl-benzo[b]thiophene-2-carbaldehyde according the procedure of Example 5 Step 5. MS (ESI) m/z 546.
Reaction SMILES: [NH:1]([C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)=[O:4])[NH2:2].CCO[C:40](OCC)(OCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(O)C>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:3]3[O:4][C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:2][N:1]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NN)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cc3nnc(-c4ccccc4)o3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
A mixture of 60 mg (0.12 mmol) of tert-butyl (3RS,4RS)-4-(4-hydrazinocarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 27.7 gl (0.12 mmol) of triethyl orthobenzoate in 5 ml of ethanol was boiled under reflux for 18 hours. After cooling the mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 30 mg (44% of theory) or tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-piperidine-1-carboxylate as a colourless foam; MS: 575 (M+H)+.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[OH:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[CH3:17])[CH:9]=1
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Oc1cc(O)ccn1
Yield: 44.3 %

Procedure:
The general procedure of Example 27 was followed using 4.0 g of 2,4-bis(trimethylsilyloxy)-pyridine and 2.92 g of 2-methylbenzoyl chloride, thereby producing 1.59 g of the title compound in a yield of 44.18%.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH:19][C:20](=O)[C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].O>O1CCCC1>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[S:33][C:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[N:19][N:18]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(CCC(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(CCc2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 126.7 %

Procedure:
A suspension of 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.0 g) and diphosphorus pentasulfide (730 mg) in tetrahydrofuran (20 ml) was stirred for 1 hour at 60° C. To a reaction mixture was added water and the mixture was stirred for 1 hour at room temperature. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give methyl 4-[5-[2-(4-n-hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoate (883 mg).
Reaction SMILES: CC(C)(O[C:5](=O)[N:6](C)[O:7][CH2:8][CH:9]([CH3:18])[O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])C>C(O)(C(F)(F)F)=O>[CH3:5][NH:6][O:7][CH2:8][CH:9]([O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:18]
Reactant: CC(CON(C)C(=O)OC(C)(C)C)OC(=O)CCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CNOCC(C)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,2,5,8-Tetramethyl-4,10-dioxo-3,6,9-trioxa-5-azatridecan-13-oic acid (227 mg, 0.744 mmol) was dissolved in 4 mL TFA. The reaction mixture was stirred at room temperature for 4 h and concentrated. The crude product was purified by silica gel flash column chromatography using 12% MeOH/dichloromethane as eluent. The desired product was obtained as a colorless gel (30 mg, 0.146 mmol, 20%). 1H NMR (CD3OD, 300 MHz): δ (ppm) 1.17 (d, 3H, J=6.6 Hz), 2.58 (s, 3H), 2.61 (s, 3H), 3.66 (d, 2H, J=5.4 Hz), 5.10-5.16 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:20]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:30][CH2:29]2)=[CH:20]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 20 °C
Yield: 20.1 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.3 g), 4(3-indolyl)piperidine (4.5 g) and sodium bicarbonate (1.9 g) in a mixture of dimethylformamide (100 cc) and tetrahydrofuran (100 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5 - 1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling methyl ethyl ketone (60 cc), 2-{3-[4-(3-indolyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g) is obtained, m.p. 162° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CO>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2pc[nH]c12
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCn1cpc2ncnc(N)c21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
7-Amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.5 g, 3.29 mmol) was suspended in dry DMF to which sodium hydride (160 mg, 4 mmol, 60% dispersion in mineral oil) was added under an argon atmosphere. The mixture was stirred at room temperature for 40 min and 1-bromohexane (0.56 mL, 4 mmol) was added. The reaction was continued for 3 h and the solvent was evaporated. The residue was dissolved in dichloromethane (150 mL) and washed with water (25 mL). Organic layer was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer was dried (Na2SO4) and evaporated. The residue was purified by silica gel column (2×15 cm) chromatography eluting with dichloromethane containing 0-4% methanol. The appropriate fractions containing the desired product were evaporated to yield 0.53 g (68%), mp 220-222° C. Ir (KBr): ν690 (=P-C), 1220 (-P=CH), and 3295 (NH2) cm-1. Uv (pH 1): λmax 254 nm (ε23,700), 282 (11,500), and 314 (5200); (MeOH): λmax 266 (ε31,600); (pH 11): λmax 266 nm (ε33,300), and 330 (2200). 31 p nmr (DMSO-d6): 63.21. 1H nmr (DMSO-d6): δ 0.80(t, 3 H, CH3), 1.23 (br s, 6 H, 3CH2), 1.92 (t, 2 H, CH2), 4.24 (t, 2 H, NCH2), 8.15 and 8.23 (2s, 2 H, NH2), 8.44 (d, 1 H, C5H), and 8.86 (d, 1 H, J=58.5 Hz, C2H). Anal. Calcd. for C11H17N4P: C, 55.92; H, 7.25; N, 23.72. Found: C, 55.49; H, 7.31; N, 23.28.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[CH3:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[CH3:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: Cc1cc(-n2ccccc2=O)ccc1N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: Cc1cc(-n2ccccc2=O)ccc1NC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
70.1 Using general method G, 1-(4-amino-3-methyl-phenyl)-1H-pyridin-2-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. Pale grey solid.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[Na].[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([CH2:34][C:35]([O-])=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([C:34]3[C:35](=[O:36])[N:12]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[C@@H:11]4[C@H:6]([C:4]=3[OH:3])[C@@H:7]3[CH2:21][C@H:10]4[CH2:9][CH2:8]3)=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2cc(Br)cnc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(C2=NS(=O)(=O)c3cc(Br)cnc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reaction time: 0.02 h
Yield: 60.3 %

Procedure:
(1S,2R,3S,4R)-3-(4-Fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 0.213 g, 0.73 mmol), sodium-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-acetate (0.25 g, 0.73 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.305 g, 0.803 mmol) were combined and dissolved in N,N-dimethylformamide (1.5 mL). The mixture was shaken vigorously for about 1 min until everything dissolved. The solution continued to stir for 1 h. Triethylamine (0.5 mL, 3.65 mmol) was added and the mixture was stirred at 50° C. for 16 h. The mixture was concentrated in vacuo to a volume of −5 mL. Water (˜20 mL) was added and the product precipitated. The solid was collected by vacuum filtration and purified by flash column chromatography (Merck silical gel 60, 40-63 μm; 35% ethyl acetate in hexanes) to afford the desired product, (0.24 g, 0.44 mmol, 60%) as a white, brittle foam. A portion of the product (0.07 g, 0.128 mmol) was recrystallized from n-propanol (0.5 mL) to afford the pure desired product, 5-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.044 g, 0.081 mmol, 63%), as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.23 (2H, m), 1.38-1.60 (4H, m), 2.51 (1H, s), 2.63 (1H, s), 3.00 (1H, d, J=8.4 Hz), 3.55 (1H, d, J=9.4 Hz), 4.41 (1H, d, J=14.7 Hz), 4.95 (1H, d, J=15.4 Hz), 7.14 (2H, t, J=9.0 Hz), 7.33 (2H, dd, J1=8.6 Hz, J2=5.5 Hz), 8.66 (1H, s), 8.82 (1H, s). LC-MS (ESI) calcd for C23H20BrFN4O4S 546.04, found 547.2 [M+H+].