Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>O1CCOCC1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C)cc4o3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3F)oc2c1
Temperature: 50 °C
Yield: 15 %

Procedure:
To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF (20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1 H), 8.00-7.60 (m, 6 H), 7.30 (d, 2 H), 7.00 (d, 1 H), 4.05 (m, 1 H), 3.20 (m, 1 H), 2.40 (s, 3 H), 2.20 (m, 1 H), 1.95 (m, 1 H), 1.80-1.60 (m, 4 H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][OH:12])[CH:6]=[C:7]([F:9])[CH:8]=1.FC(F)(F)C(O)=O.[F:20][C:21]([F:36])([F:35])[C:22]([N:24]1[CH2:29][C:28]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:27][CH2:26][CH2:25]1)=[O:23].C(N(CC)CC)C>C(#N)C>[F:36][C:21]([F:20])([F:35])[C:22]([N:24]1[CH2:29][C:28]2([CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:4]=[C:5]([CH2:10][CH2:11][OH:12])[CH:6]=[C:7]([F:9])[CH:8]=3)[CH2:31][CH2:30]2)[O:27][CH2:26][CH2:25]1)=[O:23]
Reactant: OCCc1cc(F)cc(CBr)c1
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of 2-(3-(bromomethyl)-5-fluorophenyl)ethanol (example 41, step b) (3.6 g) and 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (5.66 g) in acetonitrile (80 mL) was treated with triethylamine (5.38 mL) and the mixture stirred at 20° C. for 20 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 4.9 g.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[OH-:24].[Na+].Cl.[NH2:27]O.Cl>C1(C)C=CC=CC=1.O.CN1CCCC1=O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)([C:11]([F:14])([F:13])[F:12])[O:24][N:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)nc2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
1.00 g of toluene and 0.60 g of N-methyl-2-pyrrolidone was added to 0.20 g (0.47 mmol) of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.19 g of water to 0.075 g (1.88 mmol) of sodium hydroxide, and then adding the solution in which 0.036 g (0.52 mmol) of hydroxylamine hydrochloride was dissolved into 0.077 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.30 g (2.83 mmol) of 35% hydrochloric acid and 0.88 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 5 ml of toluene was added to the reaction solution and separation operation was performed. The toluene phase was washed twice with 3 ml of water. The solvent was distilled off under reduced pressure to obtain 0.18 g of 3-(6-bromopyridin-3-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 86.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:48][CH2:47]1.Cl>O>[C:57]([C:56]1[CH:55]=[CH:54][C:53]([CH2:52][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[CH2:51][CH2:50]2)=[CH:60][CH:59]=1)#[N:58]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C(=O)NC2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred mixture of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added triethylamine (2.6 ml, 18.32 mmol), HATU (2.32 g, 6.11 mmol), and 4-((4-aminopiperidin-1-yl)methyl)benzonitrile as its HCl salt (1.6 g, 5.55 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration, purified by column chromatography to yield 0.91 g (44%) of methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate as a white solid. LCMS (m/z): 379 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9](N)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[FH:25].N1C=CC=CC=1>>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]([F:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CCOc1nc(N)c2ncccc2c1Br
Reactant: F
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOc1nc(F)c2ncccc2c1Br
Temperature: 0 °C
Yield: 85 %

Procedure:
To a 100 mL round bottom flask was added 5-bromo-6-ethoxy-1,7-naphthyridin-8-amine (500 mg, 1.86 mmol), followed by pyridine hydrogen fluoride (10 mL). The mixture was cooled to 0° C. and sodium nitrite (0.154 mg, 2.24 mmol) was added in portions. The mixture was slowly warmed to room temperature over a period of 3 h. The reaction was neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-6-ethoxy-8-fluoro-1,7-naphthyridine as a pale yellow solid (430 mg, 1.59 mmol, 85%). 1H NMR (400 MHz, CDCl3): δ ppm 8.87 (d, J=3.52 Hz, 1H), 8.42 (d, J=8.79 Hz, 1H), 7.65 (dd, J=8.13, 3.30 Hz, 1H), 4.55 (q, J=7.03 Hz, 2H), 1.49 (t, J=7.03 Hz, 3H). LC/MS m/z 273 [M+H].
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:43])[C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34])=[O:31]>>[CH3:28][N:29]([CH3:43])[C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:42]=1)[CH3:34])=[O:31]
Reactant: CN(CC(=O)N(C)C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CC(=O)N(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(dimethylcarbamoyl-methyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=10:1) C29H30N4O4
Reaction SMILES: [NH2:1][C@H:2](CO)CC1N=CNC=1.[H-].[Na+].[ClH:13].[ClH:14].C[NH:16][C@H:17]([CH2:24][OH:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1.N1C=CC=CC=1>CCCCCC.CN(C=O)C>[NH3:1].[CH2:2]([Cl:14])[Cl:13].[NH2:16][C@H:17]([CH2:24][OH:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1
Reactant: Cl
Reactant: CN[C@H](CO)Cc1c[nH]cn1
Agent: N[C@H](CO)Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: ClCCl
Product: N
Reaction time: 1.5 h

Procedure:
TBDMS protected histidinol 14--To a stirred solution of 205 mg (5.1 mmol) of NaH washed 3× with hexane, under argon, in 3.0 mL DMF was added in portions 500 mg (2.3 mmol) of N-methylhistidinol dihydrochloride, resulting in moderate gas evolution. The solution was stirred for 1.5 h, then 1.8 mL (23 mmol) of anhydrous pyridine and 693.0 mg (4.6 mmol) of TBDMSC1 was added. The solution was stirred for 1.5 h, concentrated in vacuo and flash chromatographed on silica with 15% CH3OH.NH3 /CH2Cl2 to yield 14.
Reaction SMILES: [F-:1].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[CH:29]([C:31]1[CH:45]=[CH:44][C:34]([O:35][CH2:36][CH2:37][CH2:38]OS(C)(=O)=O)=[CH:33][CH:32]=1)=[O:30].O>C(#N)C>[F:1][CH2:38][CH2:37][CH2:36][O:35][C:34]1[CH:44]=[CH:45][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OCCCOc1ccc(C=O)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(OCCCF)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Potassium fluoride (Fluka, 7.2 mg, 0.124 mmol) and kryptofix 222 (Fluka, 46.7 mg, 0.124 mmol) were dissolved in dry acetonitrile (2.5 ml). After 10 min the mixture was added to a stirred solution of methanesulfonic acid 3-(4-formylphenoxy)propyl ester 13 (16.0 mg, 0.062 mmol) in dry acetonitrile (1.5 ml). The reaction mixture was heated at 60° C. for 30 minutes. The product was confirmed by analytical HPLC (column Phenomenex Luna C18(2) 3 μm 4.6×50 mm, solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 10-80% B over 10 min; flow 2.0 ml/min, UV detection at 214 and 254 nm) co-eluting with commercial standard (Fluorochem) at 5.0 minutes.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:39][CH:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>CCOC(C)=O>[CH:40]([S:42]([N:21]1[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:26]=[CH:27][N:28]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20]1)(=[O:44])=[O:43])([CH3:41])[CH3:39]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.5 %

Procedure:
2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 7.1 mg, 0.016 mmol) was suspended in DCM (90 μL, 0.018 mmol) and cooled in an ice bath. To this was added triethylamine (7.5 μL, 0.054 mmol) followed by propane-2-sulfonyl chloride (2.7 mg, 0.019 mmol). The reaction mixture was allowed to warm to ambient temperature. After 15 hours, the reaction mixture was diluted in EtOAc and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated down to afford 2-(1-(isopropylsulfonyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (4.8 mg, 0.010 mmol, 58% yield) as a light yellow oil. MS (apci) m/z=466.6 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:31][CH2:30][C:15]3[N:16]4CCO[C:18]5[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[C:22]([C:17]4=5)[C:14]=3[CH2:13]2)=[CH:4][CH:3]=1.[CH2:33]([OH:36])[CH2:34]O.CC1C=[CH:40][C:41]([S:44](O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][N:12]3[CH2:31][CH2:30][C:15]4[N:16]5[CH2:40][CH2:41][S:44][C:18]6[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[C:22]([C:17]5=6)[C:14]=4[CH2:13]3)[O:36][CH2:33][CH2:34][O:32]2)=[CH:6][CH:7]=1
Reactant: O=C(CCCN1CCc2c(c3c(C(F)(F)F)ccc4c3n2CCO4)C1)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: Fc1ccc(C2(CCCN3CCc4c(c5c(C(F)(F)F)ccc6c5n4CCS6)C3)OCCO2)cc1

Procedure:
1-(4-Fluorophenyl)-4-(6-(trifluoromethyl)-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)-1-butanone (70 mg, 0.15 mmol) and ethylene glycol (10.4 mg, 0.17 mmol) were mixed together in anhydrous toluene (5 mL) in a round bottom flask equipped with a Dean-Stark apparatus and 3 Å molecular sieves. A few crystals of p-TsOH were added and reaction was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and then extracted with dichloromethane (2×25 mL), washed with saturated sodium carbonate (1×15 mL) and brine (1×15 mL), dried (sodium sulfate) and concentrated. Product was purified by preparative thin layer chromatography on silica gel, and eluted with 10% MeOH in dichloromethane to give the title compound. 1H NMR (CDCl3, 300 MHz): δ8.00-7.95 (m, 2H), 7.10-6.92 (m, 4H), 4.30-4.26 (m, 2H), 4.03-4.00 (m, 1H), 3.79-3.71 (m, 3H), 3.28-3.23 (m, 2H), 2.92-2.82 (m, 5H), 2.73 (t, 2H, J=7.1 Hz), 2.60 (t, 1H, J=7.5 Hz), 2.10-2.05 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:13][CH2:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13
Reactant: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Br)cc2c43)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3-n3ccc4cc(Br)cc2c43)CC1
Reaction time: 36 h
Yield: 65.5 %

Procedure:
To a solution of 4-bromo-6-(4-methyl-1-piperazinyl)-1,2dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (5.7 g, 14.3 mmoles) in chloroform (100 ml) was added manganese dioxide (5 g) and the mixture was heated at gentle reflux for 24 hours. Additional manganese dioxide was added and reflux was continued for 36 hours. The mixture was filtered and the solids were washed with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was purified on a silica gel column (160 g), eluted with a mixture of methanol and dichloromethane (1.5% methanol in dichloromethane, 4 l, 2% methanol in dichloromethane, 2 l). The fractions containing pure product were combined and concentrated to give 3.7 g (64%) of product. Recrystallization from toluene (23 ml) yielded the analytical sample, mp 157°-159° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]([F:11])([F:10])[F:9])=[N:4][N:3]=1.[Cl:12][C:13](Cl)=[C:14]([Cl:17])[C:15]#[N:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][N:6]1[C:5]([C:8]([F:9])([F:11])[F:10])=[N:4][N:3]=[C:2]1[S:1][C:13]([Cl:12])=[C:14]([Cl:17])[C:15]#[N:16]
Reactant: N#CC(Cl)=C(Cl)Cl
Reactant: Cn1c(S)nnc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(SC(Cl)=C(Cl)C#N)nnc1C(F)(F)F
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a stirred mixture of 3.5 g (0.0192 mole) 3-mercapto-4-methyl-5-trifluoromethyl-1,2,4-triazole (the product of Example 6) and 3.0 g (0.0192 mole) trichloro-acrylonitrile in methylene chloride, 1.94 g (0.0192 mole) triethylamine in methylene chloride were added dropwise. The reaction mixture was stirred at room temperature for several days. The reaction mixture was washed with water and then dried over magnesium sulfate. The organic phase was passed through a short silica gel (SiO2) column and stripped to give a thick oil which soon crystallized. The material was recrystallized from methylene chloride/hexane to give 1.5 g of the above-identified product as a light yellow solid, melting point 90°-94° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][C:25]([C:35]([OH:37])=[O:36])=[C:26]([C:28]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29])[N:27]=2)[CH2:19][C@@H:18]1[O:38][CH3:39])=[O:15].C(Cl)Cl>CO>[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][C:25]([C:35]([O-:37])=[O:36])=[C:26]([C:28]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29])[N:27]=2)[CH2:19][C@@H:18]1[O:38][CH3:39])=[O:15].[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: COCCNC(=O)c1nc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)sc1C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC[NH2+]CC
Product: COCCNC(=O)c1nc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)sc1C(=O)[O-]
Reaction time: 0.08 h

Procedure:
Diethylamine (0.0058 mL, 0.056 mmol, Aldrich) was added to a suspension of 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(2-methoxyethyl)amino]carbonyl}-1,3-thiazole-5-carboxylic acid (0.03 g, 0.056 mmol, Example 387) in methanol (5 mL). After stirring five minutes, methylene chloride was added until solution was homogeneous. The reaction was concentrated and the resulting solid was dried overnight (0.024 g). MS (ES) MH+: 534 for C24H37Cl2N6O6S; NMR: 1.16 (t, 3 H) 1.74 (s, 2 H) 2.19 (s, 3 H) 2.91 (q, 3 H) 3.25 (s, 3 H) 3.32 (s, 4 H) 3.37 (s, 3 H) 3.42 (d, 2 H) 3.53 (s, 1 H) 3.94 (s, 1 H) 4.22 (s, 2 H) 7.17 (d, 1 H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C)C=O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCCCCCCBr
Reactant: COC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)OCCCCCCBr
Yield: 22.2 %

Procedure:
To 120 ml of dry N,N-dimethylformamide, 4.0 g of 60% sodium hydride was added. To the mixture was added dropwise 11.81 g of methyl 2-hydroxyisobutyrate with stirring under ice-cooling, and stirred for 10 minutes. Then, 122 g of 1,6-dibromohexane was added and stirred for 15 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=20:1) to provide 6.25 g of the objective compound as yellowish oil.
Reaction SMILES: [N+]([O-])([O-])=[O:2].[Ce+3:5].[N+]([O-])([O-])=[O:7].[N+]([O-])([O-])=[O:11].N[C:15](N)=[O:16].[OH2:18]>>[C:15](=[O:16])([O-:11])[O-:18].[Ce+3:5].[C:15](=[O:16])([O-:7])[O-:18].[C:15](=[O:16])([O-:2])[O-:18].[Ce+3:5]
Reactant: O
Reactant: NC(N)=O
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+3]
Product: O=C([O-])[O-]
Temperature: 140 °C

Procedure:
43.4 kg of cerium nitrate and 18 kg of urea were mixed at atmospheric pressure (1 atm) and room temperature, and then reacted for 16 hours in a reactor that was heated to 140° C. Subsequently, the resultant was slowly cooled and diluted with water, leading to termination of the reaction, and then dried under vacuum at 80° C. for 24 hours to obtain a cerium carbonate-based compound.
Reaction SMILES: C(Cl)Cl.N1C=CC=CC=1.[CH2:10]([O:17][C:18]1[C:19]([CH3:33])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C@:23]([CH3:32])([CH2:30][OH:31])[CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[C:19]([CH3:33])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C@:23]([CH3:32])([CH:30]=[O:31])[CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CO)O2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(C=O)O2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred mixture of 36 ml. of dry CH2Cl2, 2.8 ml. of dry pyridine and 1.46 g. (14.6 mmol) of CrO3 was added a solution of 645 mg. (1.98 mmol) of (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanol in 5 ml. of CH2Cl2. The dark mixture was stirred for 40 min. at room temperature then the organic solution was decanted and the dark residue was washed with ether and CH2Cl2. The combined organic solutions were diluted with ether, washed with 1 N NaOH, H2O and 1 N HCl and work-up was then completed in the usual manner. The yellow oily product (590 mg.) was chromatographed on 50 g. of silica gel. Elution with 19:1 (parts by volume) hexane-ether gave 492 mg. (76.7%) of pure (S)-(+)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-carboxyaldehyde as an oil which crystallized yielding a colorless solid, mp 56°-58°; [α]25D+11.89° (c 5.2, CHCl3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>C1COCC1>[C:17]1([CH:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[C:14](=[O:16])[CH3:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCNCC1c1ccccc1
Reaction time: 2 h
Yield: 119.4 %

Procedure:
To a solution of 4-acetyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.82 mmol) in THF (3 mL) at 0° C. was added 50% TFA/dichloromethane (1 mL). After stirred for 2 h, the reaction mixture was concentrated in vacuo. The residue was diluted with dichloromethane and silica-bound carbonate (2 g, 0.77 mmol/g, Silicycle, Inc.) was added. The reaction mixture was stirred overnight, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (10/1 dichloromethane/methanol with 1% triethyl amine) to provide 1-(2-phenyl-piperazin-1-yl)-ethanone (200 mg, 119%). (M+H)+=205 m/e.