Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 77 %

Procedure:
To a solution of the above-mentioned crude product tert-butyl{3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate in ethanol (80 mL)/tetrahydrofuran (20 mL) was added 10% palladium-carbon (1.54 g), and the mixture was stirred at room temperature for 7 hr under a hydrogen atmosphere (1.0 pressure). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound (3.35 g, 77%) as brown crystals.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:1]=[N:3][CH:4]=[C:5]2[CH:10]=1)=[O:15]
Reactant: COC(=O)CCCc1ccnc(CNC=O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCCc1ccn2cncc2c1

Procedure:
2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)pyridine (33 mg) is dissolved in 1 ml of toluene and heated at 90° with phosphorus oxychloride (44 mg) for 18 hours under nitrogen. The solvent is evaporated and the residue is suspended in methylene chloride, cooled to 0° and made basic with saturated ammonium hydroxide solution. The aqueous phase is extracted with methylene chloride (4×15 ml) which is dried over sodium sulfate and evaporated to yield 7-(3-methoxycarbonylpropyl)imidazo[1,5-a]pyridine as an oil, after purification by preparative thin layer chromatography (silica gel, 3:1 ethyl acetatemethanol); NMR (CDCl3) 3.70 (s, 3 1 H), 6.45 (q, 1 H), 7.2 (s, 1 H), 7.32 (s, 1 H), 7.90 (d, l H), 8.08 (s, 1 H); IR (CH2Cl2) 1730 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(NC(C)C)(C)C.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:27](=[O:28])[O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccc(NC(=O)Oc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 4-methoxy-2-nitroaniline (15.0 g) and diisopropylamine (16.2 ml) in dichloromethane (300 ml) was added dropwise under ice-cooling a solution of phenylchloroformate (16.8 g) in dichloromethane (30 ml). The reaction solution was stirred at room temperature overnight, washed with water and saturated saline and dried over anhydrous MgSO4. The solvent was distilled off. Crystallization of the residue from hexane gave phenyl 4-methoxy-2-nitrophenylcarbamate (12.6 g, 49.1%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:12]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)c1ccc(N)c(N)c1

Procedure:
2 G. of 1-amino-4-methylsulfonyl-2-nitrobenzene is treated in 200 ml. methanol with hydrogen at 4 atmospheres pressure in the presence of Raney nickel catalyst. The catalyst is removed by filtration and the filtrate concentrated to yield 1,2-diamino-4-methylsulfonylbenzene.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]=[CH:12][C:11]([I:14])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=1.[O-]CC.[Na+]>C(O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:25]([CH2:2][C:3]1[N:13]=[CH:12][C:11]([I:14])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=1)(=[O:23])=[O:24])[CH3:31]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc(I)cnc1CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN(Cc1ncc(I)cc1C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(bromomethyl)-5-iodonicotinate (Preparation 10, 9.25 g) and ethyl (((4-methylphenyl)sulfonyl)amino)acetate (7.0 g) are dissolved in anhydrous ethanol (50 mL) and a solution of sodium ethoxide (3.4 g) in ethanol (45 mL) is added over 15 min. The mixture is stirred overnight and then poured into ice water. The mixture is extracted with ethyl acetate (3×100 mL) and the organic layer is concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]#[C:20][Si](C)(C)C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:25]#[N:26])[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]#[CH:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:25]#[N:26])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To 800 mg of 4-(3-bromo-phenylamino)-6-trimethylsilanylethynyl-[1.7]naphthyridine-3-carbonitrile in 20 mL of tetrahydrofuran at 0° C. under an inert atmosphere was added 2.5 mL of 1 M tetrabutylammonium fluoride/tetrahydrofaran. After 1 hour at ambient temperature, the reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried with sodium sulfate and evaporated. The product was purified by flash chromatography on silica gel to give 300 mg of 4-(3-bromo-phenylamino)-6-ethynyl-[1.7]naphthyridine-3-carbonitrile: melting point 224° C. (decomposed); mass spectrum (m/e): M+H 349.1, 351.1.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:33]=[CH:32][C:15]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[OH-].[Ba+2].[OH-].[O:37]1CCOCC1>O>[OH:37][CH2:2][CH2:1][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:33]=[CH:32][C:15]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:29])[CH3:30])[C:26]([CH3:31])=[N:25][CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5]
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Reactant: C1COCCO1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(=O)(=O)CCO)CC4)cc3)n2)n1C(C)C

Procedure:
A mixture of 2-{4-[4-(vinylsulphonyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl) pyrimidine (Example 29; 260 mg 0.56 mmol) and barium hydroxide (560 mg 3.27 mmol) in water (10 ml) was heated at 65° C.-90° C. over 6 hours. 1,4-dioxane (1 ml) was added after 1, 2, 3 and 5 hours. After evaporation under reduced pressure, the residue was treated with water (10 ml) and saturated sodium hydrogen carbonate solution (10 ml). The suspension was extracted with DCM (30 ml and 2×20 ml) and EtOAc (25 ml). Both extracts were washed (separately) with brine (10 ml) and dried (Na2SO4). The extracts were combined and evaporated. After chromatography on silica gel using MeOH:DCM (4:96 to 8:92), the title compound was obtained as a yellow solid (108 mg 40%). NMR: 1.40 (d, 6H), 2.49 (s, 3H), 3.13 (m, 4H), 3.23 (t, 2H), 3.30 (m, 4H), 3.76 (q, 2H), 5.01 (t, 1H), 5.69 (septuplet, 1H), 6.93 (d, 2H), 6.96 (d, 1H), 7.39 (s, 1H), 7.48 (d, 2H), 8.31 (d, 1H), 9.18 (s, 1H); m/z 486.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=[O:3].[Na+].C(OCC)(=O)C.Cl>O>[C:2]([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[CH:10]([NH:13][C:14](=[O:15])[CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 99.7 %

Procedure:
21.6 g of sodium cephalothin was dissolved in 500 ml of water and layered with 500 ml ethyl acetate. The mixture was acidified to pH4 by addition of 6N HCl and the product was extracted into the ethyl acetate phase, which was dried (MgSO4) and evaporated in vacuo to yield 20.4 g of 3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid, mp 152°-154°.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][CH2:6][CH2:7][OH:8].C(S[C:13]1[N:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:17]=2[N:18]=1)CC.O>O1CCCC1>[CH3:3][S:4][CH2:5][CH2:6][CH2:7][O:8][C:13]1[N:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:29][CH:30]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:17]=2[N:18]=1
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CSCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSCCCOc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (5 ml) was added 3-(methylsulfanyl)propan-1-ol (0.206 ml) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (acetic acid ethyl/hexane) to give the title compound (96 mg).
Reaction SMILES: [P:1]([O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][C:35]4[N:36]=[C:37]([C:40]5[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=5)[O:38][CH:39]=4)=[CH:28][CH:29]=3)[O:24][CH:23]=2)=[CH:18][CH:17]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][C:35]4[N:36]=[C:37]([C:40]5[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=5)[O:38][CH:39]=4)=[CH:28][CH:29]=3)[O:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCOc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-c2ccc(OCOP(=O)(O)O)cc2)coc2cc(OCc3coc(-c4cc(F)cc(C(F)(F)F)c4)n3)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 50 mL round bottomed flask ditert-butyl {4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenoxy}methyl phosphate (119.1 mg, 0.166 mmol) was treated with trifluoroacetic acid (37.9 mg, 0.332 mmol, 2.0 equiv) in methylene chloride (2 ml). The mixture was stirred at room temperature for 18 hours, methylene chloride (10 ml) added, and the suspension thus obtained was filtered through a glass filter. The residue on the filter was collected to give {4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenoxy}methyl dihydrogen phosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)=[O:5].[CH2:23]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:29][CH:30]=2)[CH:19]=[CH:18][C:3]=1[C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=1)=[O:5]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCc1ccc(OC(=O)c2ccc(O)cc2Cl)cc1
Solvent: c1ccncc1
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(CCCCC)cc3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
A mixture of 4-pentylphenyl 2-chloro-4-hydroxybenzoate (0.0075 mole) prepared as in Example 1 and p-pentylbenzoyl chloride (0.0075 mole) in pyridine (35 ml.) is stirred at room temperature for 5 hours. The reaction mixture is then poured into ice-water. The product is filtered and washed with water to give 4-n-pentylphenyl 2-chloro-4-(4-pentylbenzoyloxy)benzoate (3.1 g., 84%), m.p. 38°-122°C. The analytical sample, m.p. 39°-122°C is obtained by chromatography on Florisil and crystallization from ethanol. The theoretical values calculated for C30H33ClO4 and the values actually found are as follows:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[NH:18]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.[OH-].[Na+]>[OH:23][C@H:20]1[CH2:21][CH2:22][N:18]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)[CH2:19]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(N2CC[C@H](O)C2)CC1
Reaction time: 16 h
Yield: 103.4 %

Procedure:
A solution of phenylmethyl 4-oxo-1-piperidinecarboxylate (1 g, 4.29 mmol) and (3S)-3-pyrrolidinol (0.411 g, 4.72 mmol) in 1,2-dichloroethane (14.29 mL) was treated at room temperature under air with sodium triacetoxyborohydride (1.363 g, 6.43 mmol) and glacial acetic acid (0.245 mL, 4.29 mmol). After 16 h, the mixture was diluted with 1N NaOH (75 mL) and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with brine (1×75 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford phenylmethyl 4-[(3S)-3-hydroxy-1-pyrrolidinyl]-1-piperidinecarboxylate (1.35 g, 98% yield). This material was used in the next step without further purification. MS (m/z) 305.0 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[CH:38]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:38][C:34]3[S:35][CH:36]=[CH:37][C:33]=3[CH2:32][C:31]([OH:40])=[O:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)Cc1ccsc1C=O
Product: O=C(O)Cc1ccsc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and (2-formyl-thiophen-3-yl)-acetic acid methyl ester according to the procedure of Example 66. MS (ES) m/z 531.1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][CH:25]([Cl:29])[C:26](Cl)=[O:27]>>[Cl:24][CH:25]([Cl:29])[C:26]([NH:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1)=[O:27]
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: O=C(Cl)C(Cl)Cl
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)C(Cl)Cl
Yield: 37 %

Procedure:
Using compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one (the product of step (e) in Example 1) (40 mg, 0.178 mmol) and 2,2-dichloro acetyl chloride (27.6 mg, 0.188 mmol) as starting materials, preparation following the method as described in Example 1(f) afforded white solid 20 mg, yield: 37%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([OH:24])[C@H:11]([CH3:25])[O:10][C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30].O>N1C=CC=CC=1>[C:28]([O:24][C@@H:12]1[C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][O:15][CH2:16][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:27])[C:9](=[O:26])[O:10][C@H:11]1[CH3:25])(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)C(=O)Cl
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To a solution of tert-butyl-(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-ylcarbamate (72 mg, 0.19 mmol) in pyridine (1 mL) at 0° C. was added isobutyryl chloride (80 μL, 0.76 mmol) and the solution was stirred at 0° C. for 2 h. The crude reaction mixture was warmed to room temperature, water (1 mL) was added, and the solution was stirred for 30 min. The reaction mixture was extracted with Et2O (3×) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexanes, TLC Rf=0.5) to furnish (3S,6S,7R,8S)-8-benzyl-3-(tert-butoxycarbonylamino)-6-methyl-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white foam (45 mg, 53%): 1H NMR (400 MHz, CDCl3) δ 7.31-7.11 (m, 5H), 5.14 (d, J=8.0 Hz, 1H), 5.03 (m, 1H), 4.94 (t, J=9.2 Hz, 1H), 4.66 (d, J=7.7 Hz, 1H), 3.89 (dd, J=11.7, 7.2 Hz, 1H), 3.56 (d, J=10.7 Hz, 1H), 3.46 (m, 1H), 3.35 (dd, J=11.4, 6.8 Hz, 1H), 2.71 (dd, J=13.9, 3.6 Hz, 1H), 2.58 (dt, J=13.9, 7.0 Hz, 1H), 2.25 (t, J=12.6 Hz, 1H), 2.04 (s, 1H), 1.43 (s, 9H), 1.32 (d, J=6.2 Hz, 3H), 1.21 (dd, J=7.0, 0.9 Hz, 6H); ESIMS m/z 471.9 ([M+Na]1).
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:36])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])[CH:46]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 80.1 %

Procedure:
A solution of 1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol (Example 33-(3); 0.05 g, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 35.3 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.5 mg, 0.0143 mmol) and potassium phosphate (32.6 mg, 0.15 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (41.0 mg, 78%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:24]2[B:25]([OH:32])[O:26][CH:27]([CH2:28][N+:29]([O-:31])=[O:30])[C:23]=2[CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[OH:32][B:25]1[C:24]2[C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:14][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][CH:21]=[CH:22][C:23]=2[CH:27]([CH2:28][N+:29]([O-:31])=[O:30])[O:26]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
MsCl (0.99 mL, 13 mmol) was added slowly to a solution of Et3N (2.85 mL, 20.5 mmol) and 7-(3-amino-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (1.55 g, 5.12 mmol) in CH2Cl2 (50 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 1 h and then quenched with H2O (50 mL). The mixture was extracted with CH2Cl2 and the organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc in hexane) to give the title compound as a viscous liquid: yield 500 mg (28%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34]C)=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.CO.[OH-].[Na+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(F)ccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccc(F)cc2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
The crude methyl 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 1) was dissolved in a solution THF: MeOH (1:1) (0.02 M) and to that solution 7 eq of an aqueous solution of NaOH (1N) were added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (12%).