Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.Cl>[Br:2][C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][N:8]([S:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])(=[O:30])=[O:29])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)CNc2cccc(Br)c2O1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CN(S(=O)(=O)c2ccccc2F)c2cccc(Br)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71214.9 %

Procedure:
8-Bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (518 mg, 2.14 mmol) was dissolved in 5 ml methylene chloride, to which pyridine (253.85 g, 3.21 mmol) was then added. The reaction mix was stirred at room temperature, and 2-fluorobenzenesulfonyl chloride (416.37 mg, 2.14 mmol) was added drop-wise to the reaction mix, after which stirring at room temperature was continued for 2 hours. The reaction mix was then heated to reflux for 1 hour, and cooled to room temperature. The reaction mix was diluted with 5 ml of methylene chloride and 10% aqueous HCl was added. The organic layer was separated, washed with water, then saturated NaHCO3, and dried (Na2SO4). Solvent was removed under reduced pressure, and the residue was purified via flash chromatography (EtOAc in hexane, 5% to 20%) to afford 610 g (71.3%) of 8-bromo-4-(2-fluoro-benzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine as an oil which solidified upon standing. MP: 108.0–110.1° C. MS: (M+H) 401.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:20](=[O:40])[CH2:21][CH2:22][C:23](=[O:39])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42]1.C(ON(CCOCCOCCOC)C(=O)CCC(O)=O)C1C=CC=CC=1>N1C=CC=CC=1>[CH2:32]([O:31][N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:39])[CH2:22][CH2:21][C:20](=[O:40])[N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1CCC(=O)O1
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Agent: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)O
Solvent: c1ccncc1
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Yield: 95 %

Procedure:
5,16-Bis(benzyloxy)-4,12,15-trioxo-5,11,16-triaza-19,22,25-trioxahexacosanoic acid (19) was synthesized by reacting compound (18) (3.40 g, 6.07 mmol) with succinic anhydride in pyridine following the procedure of (16) to produce 3.81 g (95%) of (19) as an oil: NMR δ 1.2-1.8 (m, 6 H), 2.38-2.91 (m, 8 H), 3.07-3.83 (m, 19 H), 4.79 (s, 2 H), 4.88 (s, 2 H), 5.7 (br s, 1 H), 6.62 (br s, 1 H), 7.33 (s, 10 H). Analysis: (C34H49N3O10) C, H, N.
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[CH:4].Br[C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=[CH:15][CH:16]=1>>[F:23][C:22]([F:24])([F:25])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]#[C:3][C:2]([OH:9])([CH3:1])[CH2:5][CH:6]([CH3:8])[CH3:7])[CH:12]=1)=[O:26]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(C)(O)CC(C)C
Product: CC(C)CC(C)(O)C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of 3,5-dimethylhex-1-yn-3-ol with bromide 3 following the method described in Example 2 (except that the alkynol was added after degassing) gave 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,5-dimethylhex-1-ynyl)phenyl)propyl)acetamide as a brown oil. Yield (0.287 g, 40%): 1H NMR (400 MHz, DMSO-d6) δ 9.41 (br s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.16-7.20 (m, 3H), 5.25 (s, 1H), 3.16 (q, J=6.8 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.90-1.96 (m, 1H), 1.76 (quint, J=7.6 Hz, 2H), 1.53 (m, 2H), 1.42 (s, 3H), 0.96 (d, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:27])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)=[S:55])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 0.08 h
Yield: 18.4 %

Procedure:
After dissolving 4-dimethylaminopiperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (89.3 mg) in ethanol (2 ml), D-10-camphorsulfonic acid (55.3 mg) was added and the mixture was stirred for 5 minutes under a nitrogen atmosphere. A 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.4 ml) was then added and the mixture was stirred for 1 hour. Then, a 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.4 ml) was further added to the reaction mixture and stirring was continued for 1 hour. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=8:1), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (0.5 ml) and hexane (4.0 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (24.9 mg, 18.4%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[CH:23]([CH2:26][CH3:27])[CH2:24][N:25]=[C:20]2[C@H:19]([NH2:28])[CH2:18][CH2:17]1.[O:29]=[C:30]1[NH:38][C:33]2=[N:34][CH:35]=[CH:36][CH:37]=[C:32]2[N:31]1[CH:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[CH:23]([CH2:26][CH3:27])[CH2:24][N:25]=[C:20]2[C@H:19]([NH:28][C:45]([N:42]2[CH2:41][CH2:40][CH:39]([N:31]3[C:32]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:38][C:30]3=[O:29])[CH2:44][CH2:43]2)=[O:46])[CH2:18][CH2:17]1
Reactant: CCC1CN=C2[C@H](N)CC[C@@H](c3cccc(F)c3F)CN21
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1CN=C2[C@H](NC(=O)N3CCC(n4c(=O)[nH]c5ncccc54)CC3)CC[C@@H](c3cccc(F)c3F)CN21
Reaction time: 18 h
Yield: 42.5 %

Procedure:
Triethylamine (17 μL, 0.124 mmol) was added to a solution of the (6S,9R)-6-(2,3-difluorophenyl)-3-ethyl-2,5,6,7,8,9-hexahydro-3H-imidazo[1,2-a]azepin-9-amine (13 mg, 0.035 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (15 mg, 0.053 mmol) in dichloromethane (1 mL). After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile 30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (8 mg). MS 538.2710 (M+1).
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[C:8]([N+:13]([O-])=O)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1>C(O)(C(F)(F)F)=O.[Pd]>[CH:4]1([NH2:3])[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=2[CH2:6][CH2:5]1
Reactant: CON=C1CCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc2c1CCC2N

Procedure:
A solution of 4-nitro-indan-1-one O-methyl-oxime (5.31 g, 25.75 mmol) in 50 mL of TFA was mixed with Pd/C (150 mg) and hydrogenated at 50 psi for 14 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated to give the crude title compound, which was used in the next step without further purification. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 1.90-2.03 (m, 1H), 2.41-2.53 (m, 3H), 2.63-3.18 (m, 2H), 4.65-4.75 (m, 1H), 7.00-7.13 (m, 1H), 7.18-7.27 (m, 2H), 8.31 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Cl[CH2:45][C:46]1[N:50]=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[O:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:60][C:57]([F:58])([F:59])[C:54]1[CH:53]=[CH:52][C:51]([C:49]2[O:48][N:47]=[C:46]([CH2:45][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:13]5=[CH:14][C:15]6[O:19][CH2:18][O:17][C:16]=6[CH:20]=[C:12]5[O:11][CH2:10]4)[C:2]3=[O:21])[N:50]=2)=[CH:56][CH:55]=1
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)no2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2noc(-c3ccc(C(F)(F)F)cc3)n2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-chloromethyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (44%): 1H NMR (300 MHz, CDCl3) δ 8.22 (d, 2H), 7.76 (d, 2H), 7.30-7.18 (m, 2H), 7.06 (t, 1H), 6.91 (d, 1H), 6.51 (s, 1H), 6.40 (s, 1H), 5.88 (s, 2H), 5.17 (ABq, 2H), 4.86 (ABq, 2H); MS (ES+) m/z 508.1 (M+1).
Reaction SMILES: [Cl-].[Cl:2]C1N(C)CC[NH+]1C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCCl>[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:2])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(O)cc1
Reaction time: 24 h
Yield: 72 %

Procedure:
To 9.72 g (0.0575 mole) of 2-chloro-1,3-dimethylimidazolinium chloride, 90 ml of 1,2-dichloroethane and 6.91 g (0.05 mole) of 4-hydroxybenzoic acid were added. To the mixture, 5.06 g (0.05 mole) of triethylamine was dropwise added over 30 minutes while maintaining the temperature of the mixture at 15°-20° C. Thereafter, the reaction was carried out at 15°-20° C. for 24 hours. The reaction mass was analyzed by gas chromatography and liquid chromatography. Unreacted 4-hydroxybenzoic acid remained 1.79 g (0.013 mole). 4-Hydroxybenzoyl chloride was obtained in the yield of 72%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@@H:19]([CH3:21])[C@@H:18]([CH2:22]S([O-])(=O)=O)[C@@H:17]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#[N:43].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@H:19]([CH3:21])[C@H:18]([C:22]#[N:43])[C@H:17]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:16]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [C-]#N
Reactant: C[C@@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 80 °C
Reaction time: 6 h
Yield: 5 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-(tert-butoxycarbonylamino)-5-methylpiperidin-4-ylmethanesulfonate (1.0 equiv.) in DMF (0.10 M) was added NaCN (5.0 equiv.). The mixture was stirred at 80° C. for 6 hrs and partitioned between EtOAc and H2O. The organic layer was washed NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl ((3S,4S,5R)-1-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyano-5-methylpiperidin-3-yl)carbamate in 5% yield. LC/MS (m/z)=432.2 (MH+), Rt=0.73 min.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][CH:13]2[CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15][N:14]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:4][NH:3]1>O1CCCC1.[Pd]>[O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1Cc1n[nH]c(=O)c2c1CCCC2
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCNCC1Cc1n[nH]c(=O)c2c1CCCC2

Procedure:
A solution of EXAMPLE 257D (0.77 g, 1.6 mmol) in tetrahydrofuran (100 ml) was treated with 10% palladium on carbon (85 mg, 0.8 mmol) at room temperature under hydrogen (balloon) overnight. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography (0-15% gradient of methanol in CH2Cl2) to provide the title compound. MS (DCI/NH3) m/z 349 (M+H)+.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:30])(=[S:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:30]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:29][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2sc(-c3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.468 g, 1.26 mmol) in acetonitrile (10 mL) in a 25 mL round bottom flask was added thiobenzamide (0.164 g, 1.20 mmol) and the solution heated to reflux (19 hours). The reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and concentrated yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-phenylthiazole (0.085 g, 16%) as a fine white powder: mp 188°-189° C., 1HNMR (CDCl3) 300 mHz 8.01 (m, 2H), 7.90 (d, J=8.48 Hz, 2 H), 7.62-7.55 (m, 4 H), 7.55-7.44 (m, 3 H), 7.04 (t, J=8.85 Hz, 2 H), 3.09 (s, 3H); MS (EI-thermospray) m/z 410 (MH+). HRMS (EI) Δ=-2.0 mmu.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:36]CC6C=CC=CC=6)=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(O)(=O)C.ClCCl.CO>[H][H].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Yield: 95.6 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (7.5 g, 12.6 mmol), acetic acid (few drops), dichloromethane (50 ml) and methanol (100 ml) was added 10% Pd/C (700 mg). The mixture was agitated in hydrogen gas (40 psi) until the reaction was complete (ca. 4 hr). The solution was filtered through celite and concentrated to give a crude product as a solid. The crude product was triturated with ether, and filtered. The filter cake was dried in vacuo to yield cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (6.1 g, 95% yield). 1H NMR (dmso-d6): 10.86 (1H, br. s), 10.34 (1H, br. s), 10.04 (1H, br. s), 8.46 (1H, s), 7.84-7.80 (1H, dd), 7.66-7.62 (2H, m), 7.55 (1H, s), 7.47-7.45 (1H, m), 7.41-7.37 (1H, m), 7.24 (1H, s), 7.18-7.13 (2H, t), 3.98 (3H, s), 1.46 (4H, s).
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.O[CH2:17][CH:18]1[CH2:27][CH2:26][N:25]2[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19]1>>[S:1]1[C:5]2=[C:6]([C:13]([O:15][CH2:17][CH:18]3[CH2:27][CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19]3)=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)c1c2n(c3ccccc13)CCS2
Reactant: OCC1CCN2CCCCC2C1
Product: O=C(OCC1CCN2CCCCC2C1)c1c2n(c3ccccc13)CCS2

Procedure:
2,3-Dihydrothiazolo[3,2-a]indole-9-carboxylic acid (D15) was converted to its acid chloride and reacted with eq-2-hydroxymethylquinolizidine using a procedure analogous to that described in Example 10.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[C:10]([NH2:13])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[Cl:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:26])=[O:27])=[CH:22][CH:21]=[C:20]([F:31])[C:16]=1[C:17]([NH:13][C:10]1[CH:11]=[C:12]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:5][NH:6][C:7]2=[N:8][CH:9]=1)=[O:18]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1Cl
Reactant: Nc1cnc2[nH]nc(C3CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4CC4)c3c2)c1Cl
Reaction time: 24 h
Yield: 66.3 %

Procedure:
3-Cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.0744 g, 0.427 mmol), 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (0.139 g, 0.470 mmol), EDCI (0.0901 g, 0.470 mmol), and HOBt (0.0635 g, 0.470 mmol) were dissolved in DMF (2 mL) and stirred for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water (4 X), saturated aqueous sodium bicarbonate solution (2×), and brine, dried over sodium sulfate and concentrated. The crude product was triturated with 1:1 DCM/Et2O to afford 2-chloro-N-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6-fluoro-3-(propylsulfonamido)benzamide (128 mg, 66% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) 813.21 (s, 1H), 11.08 (s, 1H), 9.74 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 7.59-7.63 (m, 1H), 7.40-7.46 (m, 1H), 3.11-3.15 (m, 2H), 2.29-2.31 (m, 1H), 1.79-1.80 (m, 2H), 0.95-1.00 (m, 7H); MS (APCI-neg) m/z=452.2, 454.1 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl.CN(C)C=O>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=Cc1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CNCc2ccccc2Cl)CC1
Yield: 85.7 %

Procedure:
To a round bottom flask (50 mL) under nitrogen with stirring, is added N-Boc-4-(aminomethyl)-piperidine (0.500 g, 2.33 mmol), 2-chlorobenzaldehyde (0.275 mL, 0.344 g, 2.45 mmol) and sodium triacetoxyborohydride (1.483 g, 6.99 mmol) to dichloroethane (20 mL) and dimethylformamide (3 mL). Reaction is allowed to stir for 2 days. TLC (10% MeOH/DCM; starting material r.f 0.1, product r.f. 0.6). Reaction is then poured onto saturated potassium carbonate (c.a. 80 mL) and the product is extracted with ethyl acetate (c.a. 100 mL). This is dried over magnesium sulphate and concentrated in vacuo. The residue is taken up in methanol and placed on a 10 g SCX-2 column and washed with methanol. The product is eluted with 3.5M ammonia in methanol solution. The resultant solution is concentrated in vacuo to afford the N-Boc-4-(2-chlorobenzylaminomethyl)piperidine as a colourless oil (0.677 g, 86%).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:18]([NH:19][CH:20]=[O:21])[C:17](=[O:22])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].[C:23]([O-:26])(=[O:25])[CH3:24].[K+].[I-].[K+].C(Cl)(=O)C>C(Cl)Cl.O.CN(C)C=O.C(O)(=O)C>[C:23]([O:26][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:18]([NH:19][CH:20]=[O:21])[C:17](=[O:22])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Yield: 64 %

Procedure:
Glacial acetic acid (5 ml) and N,N-dimethylformamide (125 ml) were added to a mixture of 2,2,2-trichloroethyl 3-bromomethyl-7β-formamidoceph-3-em-4-carboxylate, 1β-oxide (17.715 g, 25 mmole) and potassium acetate (12.25 g, ca. 125 mmole). The resulting mixture which darkened rapidly was stirred at ca. 20° for 1 hour when potassium iodide (30 g, 180 mmole) and acetyl chloride (13 ml, 0.183 mole) were added with stirring. The temperature of the reaction mixture rose to ca. 50°. After stirring for 15 minutes, M-sodium thiosulphate solution (30 ml) was added and the reaction mixture was diluted with methylene chloride (500 ml) and water (1 1) and shaken vigorously. The aqueous layer was re-extracted with methylene chloride (2 × 100 ml) and the combined organic phases were washed with water (300 ml) containing M-sodium thiosulphate solution (10 ml), and then water (3 × 300 ml). Each of these washings was acidic (pH 3) and contained suspended brown flocculent material. The dark brown methylene chloride solution was dried and filtered through a column of Kieselgel G (30 g) when much of the colour was retained. The eluate was evaporated and the residue was dissolved in ethyl acetate (100 ml), washed with water (2 × 200 ml) and evaporated to give the title ester as a brown foam (6.9 g, 64%), [α]D + 59° (CHCl3), λmax 265 nm (ε 6,800), νmax (CHBr3) 3430 (NH), 1790 (azetidin-2-one), 1745 (CO2R) and 1700 and 1510 cm-1 (CONH), τ (CDCl3) 1.76 (1H,s; CHO), 3.29 (1H,d, J 9.5 Hz; NH), 4.09 (1H,dd, J 9.5,5 Hz; C7 -H), 4.97 (1 H,d, J 5 Hz; C6 -H), 4.86, 5.16 (2H, Ab-q,J 14 Hz; C3 -CH2OCOCH3), 4.99, 5.25 (2H, AB-q, J 12 Hz; CH2CCl3), 6.36, 6.60 (2H, Ab-q, J 18 Hz; C2 -H2), 7.91 (3H,s; OCOCH3).