Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.C[Si]([C:26]#[N:27])(C)C>[I-].[Zn+2].[I-].CCOCC>[C:26]([C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:27]
Reactant: O=C1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: N#CC1=CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reaction time: 15 h
Yield: 43.6 %

Procedure:
N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide (4.21 g, 14 mmol), trimethylsilyl cyanide (10.0 g, 100 mmol) and Zinc Iodide (0.25 g) were combined and stirred under nitrogen for 15 hours. The reaction mixture was then diluted by addition of 200 mL of Et2O, washed with cold water, and the organic layer was dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in 250 mL of toluene, and 0.5 g of paratoluene sulfonic acid was added. The reaction mixture was refluxed for three hours, cooled, and the the solvent was removed under reduced pressure. The crude product was eluted through silica under medium pressure with 5% EtOAc in hexanes to yield 1.89 g (6.1 mmol, 44%) of N-(5-Cyano-7,8-dihydro-naphthalen-2-yl)-bezenesulfonamide as an oil. MS: 311 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:10])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].[Br:11]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:1]([O:5][CH2:6][CH:7]([CH3:10])[CH2:8][Br:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(CO)COC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(CBr)COC(C)(C)C
Yield: 35 %

Procedure:
Reaction of rac.-3-tert. butoxy-2-methyl-1-propanol with bromine-triphenylphosphine using the procedure of Example 28 gave rac.-3-tert. butoxy-2-methyl-1-bromopropane in 35% yield as a colorless liquid, b.p. 67°-77° C. (bath temperature) (9 mm Hg.).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(Cl)(Cl)Cl.[CH3:23][O:24][C:25]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH:12][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=3[O:24][CH3:23])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2[N+](=O)[O-])C(=O)NC(=O)C3(C)C)c(OC)c1

Procedure:
2.7 gm of 4,4-dimethyl-7-amino-8-nitro-2H,4H-isoquinoline-1,3-dione were admixed with 50 ml of chloroform and 2.5 ml of triethylamine. Subsequently, 2.2 gm of 2,4-dimethoxybenzoylchloride were added, and the mixture was refluxed for 2 hours. After cooling the solution was evaporated and the precipitate was suction-filtered off and digested with water while heating.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[B:5]1([OH:15])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][O:6]1>>[N+:1]([C:12]1[CH:13]=[CH:14][C:9]2[CH2:8][CH2:7][O:6][B:5]([OH:15])[C:10]=2[CH:11]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: OB1OCCc2ccccc21
Product: O=[N+]([O-])c1ccc2c(c1)B(O)OCC2
Temperature: -42.5 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To 4.0 mL fuming HNO3 at −45° C. was added 3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (497 mg, 3.4 mmol) in small portions while maintaining the reaction temperature between −40 to −45° C. Once the addition was complete the resulting solution was allowed to stir at −45° C. for an additional 10 min before poured into crushed ice (20 g). The ice mixture was allowed to warm up to room temperature gradually and the precipitate was collected by filtration and washed with H2O to give 7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a white powder. 1H NMR (acetone) δ: 8.51 (d, J=2.5 Hz, 1H), 8.24 (dd, J=8.3, 2.6 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.19 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2H). Amount obtained: 286 mg, 44% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH3:14][NH2:15]>CC#N>[Cl:13][C:4]1[CH:3]=[C:2]([NH:15][CH3:14])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CN
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)cc1NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A 0° C. solution of ethyl 4,6-dichloronicotinate (5 g, 22.8 mmol) in MeCN (30 mL) was treated drop-wise with aqueous methylamine (65%, 5.2 g, 45.6 mmol), warmed to RT and stirred for 8 h. The mixture was concentrated to dryness, the residue suspended in H2O and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give ethyl 6-chloro-4-(methylamino)nicotinate (4 g, 82% yield), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.04 (d, J=4.5 Hz, 1H), 6.71 (s, 1H), 4.27 (q, J=6.9 Hz, 2H), 2.85 (d, J=5.1 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][S:11][CH:12]=1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1[N:27]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([C:9]3[C:8]([CH3:7])=[CH:12][S:11][CH:10]=3)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[O:19][N:29]=1
Reactant: Cc1cscc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3cscc3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.26 mmol; 3 eq.), Intermediate 32 (120 mg; 0.42 mmol; 1 eq.), Intermediate 1 (70 mg; 0.42 mmol, 1 eq.) and DIEA (217 μL; 1.26 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) followed by crystallization from n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@@:3]([CH2:17][S@:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=O)([OH:16])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])([CH3:7])[CH3:6].[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[F:28][C:2]([F:1])([F:27])[C@@:3]([CH2:17][S:18][C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)([OH:16])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])([CH3:6])[CH3:7]
Reactant: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a suspension of (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (1.42 g, 3.41 mmol) and sodium iodide (1.53 g, 10.2 mmol) in 25 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (2.41 mL, 17.1 mmol) in 5 mL of anhydrous acetone via a syringe dropwise over 5 minutes. A greenish brown mixture was formed instantaneously. After 15 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite solution and neutralized with saturated aqueous sodium carbonate solution. The brown color disappeared and the crude was concentrated to remove most of the acetone solvent. The resulting material was diluted with 50 mL of water and extracted with three 100 mL portions of ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol as a yellow oil (1.37 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][C:24]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37]CC)=[O:36])[CH2:30][CH2:29]4)([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1.[Li+].[OH-]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:49])([F:48])[F:50])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:22][CH2:23][C:24]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]4)([CH3:27])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCN(C2(C)CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC1(N2CCN(CC(=O)O)CC2)CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1

Procedure:
Prepared analogously to Example 19.1 from 100 mg (0.12 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl -piperazin-1-yl)-4-methyl-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 10.0 mg (0.42 mmol) LiOH.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=S)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:26]>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[NH:26])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1
Reaction time: 20 h

Procedure:
To a stirring suspension of N-(3-benzyloxy-2-pyridyl)-N'-(4-chlorophenyl)thiourea (1.5 g, 0.00406 mol) in ammonia-saturated methanol (30 ml) was added yellow mercuric oxide (2.2 g, 0.01 mol). Stirring was continued for 20 h, then the solvent evaporated and the black residue treated with chloroform and filtered through celite. The filtrate was evaporated to a whim solid, which was recrystallised from ethyl acetam. Yield 0.76 g (53%), m.p. 170°-172 ° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].[H-].[Na+].Br[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[CH:11]=3)[N:6]([CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([O:1][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:3]=3)[C:7](=[O:29])[N:8]=2)=[CH:21][CH:22]=1)([CH3:27])[CH3:28]
Reactant: COCCOCCBr
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOCCOC)c1
Temperature: 60 °C

Procedure:
To a solution of 100 mg (0.236 mmol) of 1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in anhydrous DMF (5 mL) is added NaH (11 mg, 0.471 mmol) and the solution is allowed to stir until evolution of gas ceases. 1-bromo-2-(2-methoxyethoxy)-ethane (34 μl, 0.247 mmol) is added and the mixture is heated for 20 hours at 60° C. After cooling to room temperature, the reaction mixture is quenched with water and extracted with dichloromethane (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow solid which is purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (1:1) to provide the title compound as a yellow oil. Yield: 111 mg (85%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:26][CH2:25]C[NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:23]2[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Clc1nccc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Temperature: 110 °C
Yield: 53.5 %

Procedure:
To a suspension of 7-bromo-1-chloroisoquinoline (3.14 g, 13 mmol) in DMSO (20 mL) at room temperature was added either carboxylic acid tert-butyl (BOC)piperazine (7.23 g, 38.8 mmol) or BOC-homopiperazine (7.77 g, 38.8 mmol) and then potassium carbonate (5.36 g, 39 mmol). The mixture was heated to 110° C. for 24 h. On cooling, the mixture was poured onto ice/water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water 50 mL) and brine (50 mL). Before drying over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product. Purification was performed by applying the crude material to a plug of silica in a filter funnel and eluting with heptane/ethyl acetate (2:1) and gave 2.73 g (54%) yellow oil. 1H NMR (CDCl3) δ 8.20-8.22 (m, 1H), 8.13-8.18 (d, J=6 Hz, 1H), 7.65-7-71 (dd, J=12, 3 Hz, 1H), 7.59-7.65 (d, J=12 Hz, 1H), 7.21-7.25 (m, 1H), 3.64-3.73 (m, 4H), 7.27-7.36 (m, 4H), 1.49 (s, 9H); LCMS: 392, 394, 395.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@@H:33]([NH:37]C(=O)C2C=CC(C)=CC=2)[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@H:33]([NH:37][S:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)NS(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Triethylamine (21 ml, 0.15 mmol) and 4-fluorobenzenesulfonyl chloride (29 mg, 0.15 mmol) were added to a solution of 1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (50 mg, 0. 15 mmol) [prepared as described in Example 1 above] in methylene chloride (1.5 ml). The reaction mixture was stirred for 2 h, then concentrated. Purification by flash chromatography with 20:1 methylene:methanol as the eluant gave N-{1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamide (49 mg) as a solid.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[OH:24][CH2:23][C@@H:22]1[CH2:26][C@@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2CO)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To 2 l of tetrahydrofuran (THF) was added 57.6 g (1523 mmol) of sodium borohydride and the mixture was cooled to 10° C. before 250 ml (1980 mmol) of borontrifluoride etherate was added dropwise over a period of 1 hour. Then 215.3 g (755.4 mmol) of 1-(4-toluenesulfonyl)-4-hydroxy-L-proline was added carefully in 100 ml of THF and the mixture was allowed to stir for 16 hours. The reaction was quenched with methanol and 10% aqueous hydrogen chloride solution was added and the mixture was gently heated to 60° C. for 1 hour. The reaction mixture was filtered and the pH was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 164 g of the product as a white solid in 85 % yield. M.P. 132°-133° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.B(F)(F)F.[CH3:16]COCC>CO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH3:16])=[O:10])[CH:3]=1
Reactant: CCOCC
Reactant: Cc1cc(CCC(=O)O)no1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)CCc1cc(C)on1

Procedure:
A mixture of 75.4 g of 5-methyl-3-isoxazolepropanoic acid, 150 ml of boron trifluoride etherate and 400 ml of methanol was heated at reflux for eight hours. The reaction mixture was concentrated in vacuo, made basic with sodium bicarbonate solution and extracted with methylene dichloride. The extracts were concentrated in vacuo and the residue distilled at 90°-100° C.(0.05 mm) to give 73 g of methyl 5-methyl-3-isoxazolepropanoate which crystallized to a solid, m.p. 54°-55° C.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[C:11](O)(=O)[CH3:12].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH3:12])[CH2:5][C:4]=2[CH:3]=1
Reactant: Brc1cc2c(s1)CCNC2
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2sc(Br)cc2C1
Temperature: 60 °C
Yield: 89 %

Procedure:
To a suspension of 2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.86 g, 8.50 mmol) in THF (30.6 mL) was added acetic acid (17 mL) then the reaction temperature was reduced to 0° C. and sodium borohydride (2.55 g, 42.5 mmol) was added in portions. After the addition was complete, the reaction mixture was heated at 60° C. for 1 h then the reaction mixture was cooled to ambient temperature and quenched by the addition of water. The resultant solution was partitioned between ethyl acetate (75 mL) and 1N sodium hydroxide solution (50 mL) and the layers separated. The organic phase was collected then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title compound (1.87 g, 89%). 1H NMR (MeOD, 300 MHz): 6.78 (s, 1H), 3.50 (s, 2H), 2.81 (s, 4H), 2.62 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH2:27]([CH2:29][NH2:30])[OH:28]>C1COCC1>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:30]/[CH2:29][CH2:27][OH:28])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: NCCO
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(/C=N/CCO)c(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
The title compound was synthesized by reacting 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 with ethanolamine in THF.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[N:22]=1
Reactant: OB(O)c1ccc(F)c2ccccc12
Reactant: Cc1cc(-c2cccc(Br)n2)c(C)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cccc(-c3ccc(F)c4ccccc34)n2)c(C)[nH]1
Yield: 700.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 404 mg (2.13 mmol) 4-fluoronaphthalene-1-boronic acid, 534 mg (2.13 mmol) 2-(2,5-dimethylpyrrolyl)-6-bromopyridine, 902 mg (8.51 mmol) sodium carbonate, 150 mg tetrakistriphenylphosphine, 10 mL ethanol, and 2 mL water. The reaction was refluxed overnight, cooled, poured into water, and extracted into ethyl acetate. After combining with another run on a larger scale, the combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 4.72 g (85%) of an oil.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[CH2:2]([N:11]1[C:10]2[C:5]([F:4])=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[CH:8][C:9]=2[O:13][C:12]1=[O:14])[CH3:3]
Reactant: CCI
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21

Procedure:
Prepared from iodoethane (0.61 ml, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g, 6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol) in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (1.10 g, 80%); mp 121–2° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl.[C:5]1(=O)[O:10][C:8](=[O:9])[C:7]2[CH2:11][CH2:12][CH2:13][CH2:14][C:6]1=2>O>[OH:9][C:8]1[C:7]2[CH2:11][CH2:12][CH2:13][CH2:14][C:6]=2[C:5]([OH:10])=[N:3][N:2]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: NN
Agent: Cl
Solvent: O
Product: Oc1nnc(O)c2c1CCCC2

Procedure:
25 ml of purified water was added to 1.7 ml(0.035 mol) of hydrazine monohydrate and then 7 ml(0.07 mol) of conc. hydrochloric acid was added dropwise thereto. Then, the reaction solution was warmed to boil. When the reaction mixture begins to reflux, 5.33 g(0.035 mol) of 3,4,5,6-tetrahydrophthalic acid anhydride was added thereto. The reaction solution was continuously refluxed for 3 hours and then cooled. Then, the reaction solution was treated according to the same manner as Preparation 1 to obtain the title compound as an white needle crystal.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.Cl[CH2:34][C:35]1[N:36]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:38][C:39]=1[CH3:40].O>CN(C)C=O>[CH3:40][C:39]1[O:38][C:37]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[N:36][C:35]=1[CH2:34][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4nc(-c5ccccc5)oc4C)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Sodium hydride (60%, oily, 36.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (360 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (207 mg) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (304 mg, yield: 59%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).