Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23]Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[Cl:23])=[CH:6][CH:7]=1
Reactant: ClCl
Reactant: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2ncc(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 78 %

Procedure:
4-[5-(4-Chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide from Step 2 (3.0 g, 9 mmol) was dissolved in 50 mL of acetic acid, and 9 mL of 1M chlorine in acetic acid was added dropwise. The mixture was stirred for 16 hours when sat. aq. sodium bicarbonate solution was slowly added until the mixture was neutral to pH paper. The mixture was extracted with ethyl acetate (3×50 mL), combined and washed with sat. aq. sodium bicarbonate and with brine, dried over magnesium sulfate, filtered, and concentrated. The resultant product was recrystallized from isopropanol to yield 2.6 g (78%) of a white solid: mp 168°-171° C. (dec); 1H NMR (DMSO-D6/300 MHz) 8.08 (s, 1H), 7.83 (d, J=8.7Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.46 (brs, 2H), 7.44 (d, J=8.7Hz, 2H), 7.35 (d, J=8.7Hz, 2H). Anal. Calc'd for C15H11N3SO2Cl2: C, 48.93; H, 3.01; N, 11.41. Found: C, 49.01; H, 2.97; N, 11.41.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=O)[CH3:24])=[C:4]([N+:19]([O-])=O)[C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH:7]=1.[O:26]1[C:30]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:29]C(C(O)=O)=[N:27]1>>[ClH:1].[Cl:1][C:2]1[C:3]2[NH:22][C:23]([C:24]3[CH2:29][C:30]4([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[O:26][N:27]=3)=[N:19][C:4]=2[C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])[CH:7]=1
Reactant: CC(=O)Nc1c(Cl)cc(-c2ccccc2C(F)(F)F)c(C)c1[N+](=O)[O-]
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Product: Cc1c(-c2ccccc2C(F)(F)F)cc(Cl)c2[nH]c(C3=NOC4(CCCCC4)C3)nc12
Product: Cl

Procedure:
The title compound was prepared from N-(5-chloro-2-methyl-3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-acetamide (as prepared in the previous step) and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared in Example 1, step B) according to the procedures described in Example 1, steps E through H. 1H-NMR (400 MHz, d6-DMSO) δ: 7.87 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.3 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.07 (s, 1H), 3.34 (s, 2H), 2.16 (s, 3H), 1.62-1.83 (m, 6H), 1.31-1.61 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H21ClF3N3O: 448.1 (M+H). found: 448.3.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[NH:28][C:27](=[O:41])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[NH:28][C:27](=[O:41])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Product: Cc1c(C=C2C(=O)Nc3cc(NCc4ccc(F)cc4)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 65.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one as starting materials to give 2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (44 mg, 65.1%) as a red solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]([OH:16])=[O:15])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.N.[CH2:23](O)[CH3:24]>>[CH2:23]([O:15][C:14]([C:10]12[CH2:11][CH:12]1[CH2:13][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9]2)=[O:16])[CH3:24]
Reactant: CCO
Reactant: O=C(O)C12CC1CN(Cc1ccccc1)C2
Agent: N
Agent: O=S(=O)(O)O
Product: CCOC(=O)C12CC1CN(Cc1ccccc1)C2

Procedure:
To a suspension of 3-benzyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (8.5 gm, 0.0390 mole), (prepared as described in EP 0413455A2) in ethyl alcohol (250 ml) was added conc. H2SO4 (10 ml). The resulting pale yellow solution was heated at reflux for 2 hours, cooled to 0° C. and neutralized with aqueous ammonia. The neutralized solution was concentrated and was dissolved in dichloromethane. The organic layer was washed with saturated NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and was concentrated to give the crude product which was further purified by column chromatography (100-200 mesh, silicagel), eluting the compound with 5% ethyl acetate in hexane to give the pure product as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]1[C:28]([NH2:29])=[C:27]([CH3:30])[O:26][N:25]=1.C(N(CC)CC)C>ClCCl>[CH3:23][C:24]1[C:28]([NH:29][C:12]([C:11]2[C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=3[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)=[O:14])=[C:27]([CH3:30])[O:26][N:25]=1
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Reactant: Cc1noc(C)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C)noc3C)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a suspension of 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.1 g) in dichloromethane (10 ml) was added oxalyl chloride (0.08 ml) and dimethylformanide (1 drop). The reaction was stirred at room temperature for 16 hrs, and then the solvent was removed in vacuo to yield a brown solid residue. This was taken up in dichloromethane is (30 ml) and 3,5-dimethylisoxazol-4-amine (0.05 g) was added followed by triethylamine (0.15 ml) and the reaction stirred at room temperature for 16 hrs. The solvent was removed in vacuo and the product purified by flash chromatography (eluent ethyl acetate) to yield the title compound as an off-white solid (0.016 g). TLC Rf 0.38 (ethyl acetate); Mpt 85-87° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:21][C:22]1[C:30]2[C:29](Cl)=[N:28][CH:27]=[N:26][C:25]=2[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:23]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:21][C:22]1[C:30]2[C:29]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:28][CH:27]=[N:26][C:25]=2[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 37.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (330 mg, 1.08 mmol) was treated with 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (430 mg, 1.19 mmol), cesium fluoride (33 mg, 0.22 mmol), N,N-diisopropylethylamine (1.1 mL, 6.49 mol) and 1-butanol according to Preparation 13. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 0.24 g (38% yield) of the title compound. Purity 100%.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7]NCCNC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)=[CH:5][CH:4]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[NH:52][CH:53]=[CH:54][C:47]=23)=[O:39])[CH2:34][CH2:33]1.C(=O)C1C=CC=CC=1>>[CH2:7]([NH:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[NH:52][CH:53]=[CH:54][C:47]=23)=[O:39])[CH2:34][CH2:33]1)[C:6]1[CH:29]=[CH:30][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: NC1CCN(C(=O)c2sccc2Nc2ccnc3[nH]ccc23)CC1
Solvent: O=Cc1ccccc1
Product: O=C(c1sccc1Nc1ccnc2[nH]ccc12)N1CCC(NCc2ccccc2)CC1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using (4-Amino-piperidin-1-yl)-[3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)-thiophen-2-yl]-methanone instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide and benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 432 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (1H, s) 8.93 (1H, s) 7.86 (1H, d, J=5.27 Hz) 7.70 (1H, d, J=5.27 Hz) 7.20-7.27 (3H, m) 7.11-7.19 (2H, m) 6.53 (1H, dd, J=3.51, 1.95 Hz) 6.43 (1H, d, J=5.47 Hz) 3.90 (2H, d, J=13.08 Hz) 3.57 (2H, s) 2.91 (2H, t, J=10.84 Hz) 1.63 (2H, d, J=10.35 Hz) 1.04-1.15 (2H, m)
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[O:10])=[C:4]([CH3:29])[CH:3]=1.[Cl:30][C:31](OCCl)=O>ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:30][CH2:31][N:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:7]=2[O:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][C:4]=2[CH3:29])=[CH:13][C:14]1=[O:18]
Reactant: O=C(Cl)OCCl
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(CCl)c(=O)c1

Procedure:
A solution of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) (406.3 mg, 1.0 mmol) and chloromethyl chloroformate (106.7 μL, 1.2 mmol) in dichloromethane (3.5 mL) and N,N-dimethylformamide (0.3 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried with Na2SO4, filtered and evaporated to dryness to give N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide that was used in the next step without further purification. ESI-MS m/z calc. 454.07, found 455 (M+1)+; Retention time: 0.73 minutes (1 minute run).
Reaction SMILES: [Cl:1][CH2:2][C:3]1(O)[CH2:7][S:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[N:4]1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCCl>[ClH:1].[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][N:9]([CH3:11])[CH3:10])[S:6][CH:7]=1
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN(C)Cc1nc(CCl)cs1
Product: Cl
Reaction time: 16 h

Procedure:
To a 100 ml. flask were added 2.1 g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline and 25 ml. of 1,2-dichloroethane. To the mixture was added dropwise a solution of 2.1 g. of phosphorous pentachloride and 50 ml. of 1,2-dichloroethane, while the temperature of the mixture was held in the range 17°-25°. After the addition, the mixture was stirred for 16 hours. It was then filtered, and the filter cake was washed with 1,2-dichloroethane and dried under vacuum at 50° to obtain 2.4 g. of the desired product, which was identified by nmr analysis as being substantially identical to the product of Example 5.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]2=[O:11])=[CH:15][CH:16]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Oc1ccc2ccccc2n1
Product: O=c1ccc2ccccc2n1Cc1ccc(Cl)cc1
Yield: 79.7 %

Procedure:
According to Scheme 12: The title compound was prepared from quinolin-2-ol (1 eq, 0.69 mmol, 0.10 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 1.03 mmol, 0.21 g) according to the procedure described for Example 1, Step 2. Reaction conditions: 17 hours under reflux. The residue was purified by flash chromatography on silica gel using pure CH2Cl2 as eluent to afford 1-(4-chlorobenzyl)quinolin-2(1H)-one as a white solid (0.55 mmol, 0.15 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C.C(NC1C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[N+:36](=[C:9]([C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-:37]
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccccc1F
Temperature: 0 °C

Procedure:
Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.00 g, 4.76 mmol) was dissolved in acetonitrile (14 mL) and treated with triethylamine (0.760 ml, 5.47 mmol, 1.15 equiv). The mixture was cooled to 0° C., treated with 4-acetamidobenzenesulfonylazide (1.26 g, 5.23 mmol, 1.1 equiv) and warmed to ambient temperature over 1.5 hours. The mixture was partially concentrated in vacuo, cooled to 0° C., treated with sodium hydroxide (50 mL, 1 N aqueous) and extracted with chloroform (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 85:15; hexanes:ethyl acetate) providing the titled compound as a yellow oil.
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].[Li]CCCC.C(NC(C)C)(C)C.[O:21]1[C:25](=[O:26])[CH2:24][C@H:23]2C=C[CH2:29][C@@H:22]12.CI>C1COCC1>[CH3:23][C@H:24]1[C:25](=[O:26])[O:21][C@@H:22]2[CH2:29][CH:7]=[CH:5][C@H:6]12
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1C[C@H]2C=CC[C@H]2O1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H]1C(=O)O[C@@H]2CC=C[C@@H]21
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of lithium diisopropylamide, prepared by adding nBuLi (2.5 M sol. in hexanes, 1.36 mL, 3.39 mmol) to diisopropylamine (477 μL, 3.39 mmol) in THF (15 mL) at 0° C., was added a pre-cooled solution of known (3aS,6aR)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one (+)-115 (350 mg, 2.82 mmol) in THF (5 mL+3 mL rinse) at −78° C., dropwise. The reaction mixture was stirred at this temperature for 30 min, then methyl iodide (352 μL, 5.65 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 6 h. The reaction mixture was quenched with 2 M aqueous HCl. The aqueous phase was extracted with Et2O (×3). The combined organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexanes/Et2O (5:1) to yield lactone 116 (369 mg, 95%) as a brown oil. TLC: Rf=0.54 (hexanes/EtOAc=2:1); [α]D20+54.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 5.74 (m, 1H), 5.59 (m, 1H), 5.12 (t, J=5.6 Hz, 1H), 3.13 (dd, J=3.8, 1.8 Hz, 1H), 2.65 (m, 2H), 2.52 (q, J=7.6 Hz, 1H), 1.33 (d, J=7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 180.0, 130.9, 129.4, 81.3, 53.8, 39.9, 39.2, 17.4.
Reaction SMILES: N1C=CC=C(C)C=1.C(O)(=O)[C:9](O)=[O:10].[CH2:14]([O:21][NH:22][C@H:23]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:32]([O:31][C:29]([C@@H:26]1[CH2:25][CH2:24][C@@H:23]2[CH2:28][N:27]1[C:9](=[O:10])[N:22]2[O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1cccnc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C

Procedure:
3-picoline (45 ml, 464, 4 eq) was added to a slurry of benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (50 g, 116 mmol, 1 eq) in dichloromethane (1000 ml) at 0° C., followed by a solution of triphosgene (31.0 g, 104.4 mmol, 0.9 eq) in dichloromethane (200 ml). The mixture was stirred at 0° C. until the reaction was deemed to be complete. The reaction was quenched with a solution of sodium bicarbonate (24.4 g, 290 mmol, 2.5 eq) in water (300 ml), and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic layers were washed with water. The organic layer was concentrated in vacuo to give (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid benzyl ester as a solution in dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH:7]([N:6]1[C:2]([NH:1][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:3]([C:10]#[N:11])[CH:4]=[N:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1ncc(C#N)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)n1ncc(C#N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
To a solution of 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (10.4 g) in pyridine (200 ml) was added triphenylmethyl chloride (23.2 g) at room temperature. The mixture was stirred at 60° C. for 5 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated vacuo. The residue was triturated with diisopropyl ether to give 1-isopropyl-5-tritylamino-1H-pyrazole-4-carbonitrile (19.1 g).
Reaction SMILES: C(=O)(OCC(CCCCCC)C=CC=CC=CC)N.NC1C=CC=CC=1.[C:27](=[O:55])([O:29][CH2:30][CH:31]1[C:43]2([OH:45])[O:44][N:38]([CH2:39][CH:40]3[CH:42]2[NH:41]3)[C:37]2[C:32]1=[C:33]([OH:54])[CH:34]=[C:35]([CH:46]=[N:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:36]=2)[NH2:28]>CO.[Pd]>[C:27](=[O:55])([O:29][CH2:30][CH:31]1[C:43]2([OH:45])[O:44][N:38]([CH2:39][CH:40]3[CH:42]2[NH:41]3)[C:37]2[C:32]1=[C:33]([OH:54])[CH:34]=[C:35]([CH2:46][NH:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH:36]=2)[NH2:28]
Reactant: NC(=O)OCC1c2c(O)cc(C=Nc3ccccc3)cc2N2CC3NC3C1(O)O2
Agent: [Pd]
Agent: CC=CC=CC=CC(CCCCCC)COC(N)=O
Solvent: CO
Solvent: Nc1ccccc1
Product: NC(=O)OCC1c2c(O)cc(CNc3ccccc3)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 [tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in methanol (5 ml). Aniline (0.50 ml) was added to this solution and the mixture was allowed to stand at room temperature for 3 hours to give a solution containing 6,9-dihydroxy-4-phenyliminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate. 10% Palladium on carbon (100 mg) was added to the solution, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere (4.5 atm). The mixture was filtered through cellulose powder and the filter cake was washed with methanol (20 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (65:25:4, v/v/v) to afford 4-anilinomethyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Br:19])[CH:16]=[C:17]([Br:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O.[NH2:28][NH2:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([Br:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=2[C:11]([NH:28][NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Under ice-cooling, 8.42 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one, 3.0 g of hydrazine monohydrate and 60 ml of tetrahydrofuran were mixed, and the mixture was stirred at room temperature for 3 hours. A deposited precipitate was collected by filtration, and washed successively with tetrahydrofuran and methyl t-butyl ether to obtain 4.85 g of 3-bromo-N-[4,6-dibromo-2-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[NH:15][C:14]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[I-].[CH3:27][N:28]1[C:36]2[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:38][N+](C)(C)C)=[CH:29]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:38][C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[N:28]([CH3:27])[CH:29]=2)[C:14]1=[O:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C#N)nc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C#N)nc21
Temperature: 60 °C
Yield: 78.8 %

Procedure:
To a solution of (R)-3-(5-cyano-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (60 mg, 0.18 mmol) in DMF (5 ml) were added (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (74 mg, 0.21 mmol) and K2CO3 (30 mg, 0.21 mmol) at room temperature under nitrogen atmosphere. The solution was heated at 60° C. for 18 hours. The solution was cooled and poured into water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (1×). The combined organics were dried (MgSO4), filtered and concentrated. The remaining residue was purified via silica gel flash column chromatography (Companion, 12 g silica gel, 30-50% EtOAc/hexanes) to give 70 mg (80%) of the title compound as foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH2:16]=[C:17]([CH3:19])[CH3:18].[OH-].[Na+]>CCOCC.C(COC)OC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8]([O:10][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:9]
Reactant: C=C(C)C
Reactant: O=C(O)CNc1cccs1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CNc1cccs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 12.6 g of 2-thienylaminoacetic acid, 300 ml of dimethoxyethane, 15 ml of sulphuric acid and 100 ml of isobutene is stirred at room temperature in an autoclave for 5 h and poured into a mixture composed of 800 ml of ether and 800 ml of 1N sodium hydroxide solution. The ethereal phase is separated off, and the aqueous phase is extracted twice more by shaking with 200 ml of ether each time. After drying of the ether phases over MgSO4 and evaporation of the solvent there remains a yellowish oily residue.