Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:30]([O:33][CH2:34][C:35]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[CH:37][C:36]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=[O:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:30]([O:33][CH2:34][C:35]1[C:36]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])=[CH:37][CH:38]=[CH:39][C:40]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:32])[CH3:31]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 301a (500 mg, 1.077 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (546 mg, 1.292 mmol), Pd(PPh3)4 (62 mg, 0.054 mmol), Na2CO3 aqueous solution (1.0 N, 3.55 mL, 3.55 mmol), 1,2-dimethoxyethane (4.3 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. Methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 301b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([CH3:23])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28].N1CC[CH2:34][CH2:33]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17](/[CH:23]=[CH:29]/[N:27]3[CH2:26][CH2:34][CH2:33][CH2:28]3)[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Reactant: COC(OC)N(C)C
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(/C=C/N3CCCC3)c2)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
47.3 g (0.15 mol) 4-(4-Cyano-3-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester, 43.8 mL (0.33 mol) N,N-dimethylformamide dimethylacetal and 81.9 mL pyrrolidine (0.99 mol) were mixed and the mixture was heated within 30 min to 90° C. and kept at this temperature for 2 h. All volatile content was allowed to distil off. The temperature was raised to 120° C. and kept at this temperature for 27 h. Heating was discontinued and the dark highly viscous residue was dissolved in 400 mL MTB ether, washed twice with 200 mL saturated aqueous NaHCO3 and once with 200 mL water. The organic layer was concentrated and recrystallised from isopropanol/water (245 mL/105 mL) collected and dried to yield 49.5 g (yield 83%, purity 96.4%) of 4-[4-Cyano-3-((E)-2-pyrrolidin-1-yl-vinyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH2:14])=[CH:8][CH:7]=2.[Br:17][C:18]1[N:23]=[CH:22][C:21](C(O)=O)=[CH:20][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:50]([O-])(O)=[O:51].[Na+]>C(Cl)Cl>[Br:17][C:18]1[N:23]=[C:22]([C:50]([NH:14][CH2:13][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4]([C:3]([F:2])([F:15])[F:16])=[CH:12]3)=[O:51])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5, 1 g, 3.99 mmol), 6-bromo-3-pyridinecarboxylic acid (Matrix Scientific; 0.887 g, 4.39 mmol), EDC (0.841 g, 4.39 mmol), HOBT (0.672 g, 4.39 mmol) and DIPEA (2.8 mL, 16.03 mmol) in DCM (50 mL) was stirred at room temperature for 18 hrs. The mixture was stirred well with saturated aqueous NaHCO3 solution, the organics separated and the aqueous further extracted (EtOAC×3). The combined organics were dried (Phase-Sep cartridge) and evaporated under reduced pressure to a white solid. Trituration with diethyl ether overnight and filtration afforded a crude white solid (1.16 g). A portion (88 mg) was further purified via MDAP to afford the title compound as a white solid (54 mg);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: NCCO
Product: O=S(=O)(NCCO)c1cccc(Br)c1
Yield: 97.3 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and ethanolamine (1.32 g, 22 mmol) to give the title compound (5.45 g, 99%) as a white solid. MS (ISP) 280.0[(M+H)+].
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@@H:21]([CH2:23][N:24]([CH:34]([CH3:36])[CH3:35])[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[C@H:20]([CH2:37][NH:38][CH:39]2[CH2:41][CH2:40]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@@H:21]([CH2:23][N:24]([CH:34]([CH3:35])[CH3:36])[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])=[O:26])[C@H:20]([CH2:37][N:38]([CH:39]2[CH2:40][CH2:41]2)[C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:19]1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC1CC1)C(=O)OCC[Si](C)(C)C
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)Cc1ccccc1)C1CC1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of phenylacetic acid (1.45 g, 10.53 mmol) and (3R,4S)-3-cyclopropylaminomethyl-4-{[isopropyl-(2-trimethylsilanyl-ethoxycarbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (3.2 g, 7.022 mmol) in CH2Cl2 (10 mL), are added triethylamine (1.47 mL, 10.53 mmol) and 1-hydroxy-7-azabenzotriazol hydrate (1.46 g, 10.53 mmol) followed 15 min later by N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (3.06 g, 15.78 mmol). The resulting mixture is stirred for 2 days at RT, then diluted with CH2Cl2 and poured into an aqueous 2M HCl solution. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are neutralized with an aqueous saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: hexane/AcOEt 2:1). TLC, Rf (hexane/AcOEt 1:1)=0.42. MS (LC-MS): 574.2 [M+H]+; tR (HPLC, C18 column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.49 min.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[N:5][NH:4][CH2:3]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(#N)C>[CH3:1][CH:2]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:12][CH:13]=2)=[N:5][N:4]([C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)=[O:29])[CH2:3]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC1CNN=C(c2ccc(OC(F)(F)F)cc2)O1
Solvent: CC#N
Product: CC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C(c2ccc(OC(F)(F)F)cc2)O1
Yield: 87.3 %

Procedure:
1 g of the 5,6-dihydro-6-methyl-2-(4-trifluoromethoxyphenyl)-4H-1,3,4-oxadiazine prepared above was dissolved in 10 ml of acetonitrile. 1 g of 4-(trifluoromethyl)phenyl isocyanate was added dropwise and then the resulting reaction mixture was refluxed for two hours. Evaporation of the solvent at reduced pressure afforded 1.5 g of 5,6-dihydro-6-methyl-2-(4-trifluoromethoxy-phenyl)-N-(4-trifluoromethylphenyl)-4H-1,3,4-oxadiazine-4-carboxamide as a solid which was washed with a few milliliters of acetonitrile. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[CH:24]=[CH:25][C:26]6[N:30]=[C:29]([C@@H:31]7[C@@H:36]8[CH2:37][C@@H:33]([CH2:34][CH2:35]8)[N:32]7[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:28][C:27]=6[CH:45]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)O1.Br[C:48]1[NH:52][C:51]([C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:61]([O:60][C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]1[NH:52][C:48]([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[CH:24]=[CH:25][C:26]6[N:30]=[C:29]([C@@H:31]7[C@@H:36]8[CH2:37][C@@H:33]([CH2:34][CH2:35]8)[N:32]7[C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[NH:28][C:27]=6[CH:45]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:49][N:50]=1)=[O:59])([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(B5OC(C)(C)C(C)(C)O5)ccc3-4)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 120 °C
Yield: 88.4 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (88 mg, 0.14 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (53 mg, 0.168 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol). DME (1.4 mL) was added and followed by 0.56 mL 1M NaHCO3 aqueous solution. The reaction was purged with Ar and heated to 120° C. at microwave synthesizer for 0.5 hour. The reaction was cooled to room temperature and concentrated down. EtOAc was added and washed with sat. NaHCO3 aqueous (2×) and sat. NaCl aqueous (1×). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide title compound (90 mg, 86%). MS (ESI) m/z 727 [M+H]+.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15](=[NH:17])[NH2:16])=[N:13][N:12]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:9]2=[N:10][CH:11]=1.C([N:29](CC)CC)C.O.NN>C(O)C>[F:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15](=[NH:16])[NH:17][NH2:29])=[N:13][N:12]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[F:22])[C:9]2=[N:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2ncc(F)cc12
Agent: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(NN)c1nn(CCC(F)(F)C(F)(F)F)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.62 g (0.901 mmol) of the compound from Example 9A (purity about 56%) were dissolved in 10.3 ml of ethanol, and 456 mg (4.506 mmol) of triethylamine and 70 mg (1.126 mmol) of hydrazine hydrate (80% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. This gave a crude compound which was directly reacted further.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:27]4[C:22](=[C:23]([Cl:28])[CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[ClH:28].[C:29]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:27]4[C:22](=[C:23]([Cl:28])[CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: Nc1cccc(N2CCN(CCCN3C(=O)CCc4c(Cl)cccc43)CC2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(N2CCN(CCCN3C(=O)CCc4c(Cl)cccc43)CC2)c1
Product: Cl

Procedure:
1-{3-[4-(3-aminophenyl)-1-piperazinyl]propyl}-5-chloro-3,4-dihydrocarbostyril (1 g) was dissolved in 10 ml of chloroform, 5 ml of acetic anhydride and 0.1 g of 4-dimethylaminopyridine were added, and the mixture was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and then converted to the hydrochloride form, which was recrystallized from ethanol to give 900 mg of 1-{3-[4-(3-acetylaminophenyl)-1-piperazinyl]propyl}-5-chloro-3,4-dihydrocarbostyril hydrochloride as colorless needles.
Reaction SMILES: [Br:1][CH:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[C:3]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[C:11]([Cl:18])[N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2c(ncc3ccccc23)C=CC1Br
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccc(Br)cc2c2ccccc12
Temperature: 93 °C
Yield: 75.7 %

Procedure:
36.7 g (139 mmol) 2-bromophenanthridinone and 30.7 g (147 mmol) PCl5 were added to a 1 L multi-neck flask (equipped with stir arm, condenser, and base trap) along with 350 mL POCl3 and heated at 93° C. for 16 hours (note: evolution of HCl gas was predominant—destroyed by base trap). Afterwards, the mixture was assayed to determine complete consumption of 2-bromophenanthridinone. A dean stark trap was connected to the flask to remove the solvent by ½ volume. Subsequently, equal volumes of toluene were added and distilled off to remove majority of POCl3. After the third addition of toluene, the volume was reduced to 300 mL's and the remainder of the solvent removed via rotary evaporation. The solids were then recrystallized from toluene and dried to give 30.8 g (78.6% yield, 98% assay) 2-bromo-6-chlorophenanthridine as off white solids (GC-MS confirmed).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.O.C(N(CC)CC)C.Cl[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>O1CCOCC1>[N+:33]([C:24]1[CH:25]=[C:26]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:27]=[CH:28][C:23]=1[NH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:8][CH2:9]1)([O-:35])=[O:34]
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NC2CCN(C3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A mixture of EXAMPLE 173B (22.12 g), water (43 mL), and triethylamine (43.6 mL) in 1,4-dioxane (300 mL) was stirred at room temperature until EXAMPLE 173B completely dissolved. The solution was then treated with 4-chloro-3-nitrobenzenesulfonamide, heated at 90° C. for 16 hours, cooled and concentrated. 10% methanol in dichloromethane was added, and the solution was stirred vigorously at room temperature until a fine suspension existed and the mixture was filtered.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:15][S:16][CH3:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:37][C:38]([NH2:40])=[S:39].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[NH2:40][C:38]1[S:39][CH:2]=[C:3]([CH2:4][C:5]([NH:7][CH:8]2[C:34](=[O:35])[N:10]3[C:11]([C:18]([O:20][CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:19])=[C:12]([CH2:15][S:16][CH3:17])[CH2:13][S:14][C@H:9]23)=[O:6])[N:37]=1
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Yield: 69.3 %

Procedure:
To a solution of benzhydryl 7-[4-bromoacetoacetamido)-3-methylthiomethyl-3-cephem-4-carboxylate (6.0 g) in tetrahydrofuran (30 ml) was added dropwise a solution of thiourea (0.85 g) and sodium bicarbonate (0.94 g) in tetrahydrofuran (30 ml) and water (24 ml) at 25° C. with stirring, and the stirring was continued at 28° to 30° C. for an hour. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (100 ml), followed by separating out the organic layer, which was washed twice with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to give benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH:29]2[CH2:28][CH2:27][CH:26]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=4)[NH:22][CH:21]=3)[CH2:31][CH2:30]2)[CH2:11][CH2:10]1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: COc1ccccc1N1CCCNCC1
Product: COc1ccccc1N1CCCN(C2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1
Reaction time: 8 h
Yield: 80 %

Procedure:
1-(2-Methoxy-phenyl)-[1,4]diazepane (103 mg, 0.5 mmol), 4-(5-fluoro-1H-3-indolyl)-cyclohexanone (116 mg, 0.5 mmol) 5 mL 1,2-dichloroethane and 159 mg (0.75 mmol) of NaBH(OAc), were stirred at 23° C. in a 20 mL scintillation vial for 21 h. The reaction was quenched with 2 mL 1N NaOH, the vial capped, shaken and the organic layer (bottom layer) was removed with an automatic pipet. The organics were removed in a Speed Vac and pumped down overnight to afford 169 mg (0.4 mmol, an 80% yield) of the title compound as an off-white solid. MS (ES) m/z (relative intensity): 422 (M++H, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:24].[CH3:25][O:26][C:27]([CH:29]1[CH2:33][C:32](=[O:34])[NH:31][CH2:30]1)=[O:28]>>[CH3:25][O:26][C:27]([CH:29]1[CH2:33][C:32](=[O:34])[N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=4[CH3:23])[CH2:12][CH2:11]3)=[O:9])=[CH:4][C:3]=2[Cl:24])[CH2:30]1)=[O:28]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Reactant: COC(=O)C1CNC(=O)C1
Product: COC(=O)C1CC(=O)N(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2Cl)C1
Yield: 85.3 %

Procedure:
Using (4-bromo-3-chlorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (2.90 g) described in Preparation Example 171 and 5-oxopyrrolidine-3-carboxylic acid methyl ester (1.00 g) and by the reaction and treatment in the same manner as in Example 1, 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid methyl ester (2.80 g) was obtained. The so obtained 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid methyl ester (1.40 g) was dissolved in methanol (6 mL), 1N aqueous sodium hydroxide solution (6 mL) was added, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was cooled, neutralized with 1N hydrochloric acid (6 mL), 1-methylpiperazine (0.33 mL) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.00 g) were added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(4-methylpiperazine-1-carbonyl)pyrrolidin-2-one. The obtained 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(4-methylpiperazine-1-carbonyl)pyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.75 mL) was added, and the precipitate was collected by filtration to give the title compound (0.74 g).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@:13]32[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)=[CH:4][CH:3]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:26][C:27]1([F:33])[CH2:32][CH2:31][N:30]([C:2]2[CH:15]=[C:14]3[C:5]([O:6][C:7]4[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=4[C@:13]43[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: FC1(F)CCNCC1
Reactant: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(N3CCC(F)(F)CC3)ccc1O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A vial was charged with (S)-7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (200 mg, 0.509 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), 4,4-difluoropiperidine hydrochloride (160 mg, 1.017 mmol) and 1 ml of THF. The mixture was cooled to 0° C. and LHMDS (1M in THF; 2035 μL, 2.035 mmol) was added. The vial was sealed and stirred at room temperature for 2 hr. At this point more chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), (18.53 mg, 0.025 mmol) was added followed by LHMDS solution (1 ml) and stirring was continued for another hour. The mixture was quenched by addition of 2 ml of water and extracted with ethyl acetate. The combined organic layers were concentrated and purified by chromatography (5-50% DCM/MeOH/NH4OH (90:10:1) to afford (S)-7′-(4,4-difluoropiperidin-1-yl)-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (130 mg, 0.300 mmol, 59.0% yield) as yellowish foam.