Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:29]([F:32])([F:31])[F:30])=[C:20](Cl)[N:19]2[N:34]=[CH:35][N:36]=[C:18]2[N:17]=1>ClCCl>[Cl:15][C:16]1[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:29]([F:32])([F:30])[F:31])=[C:20]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[N:19]2[N:34]=[CH:35][N:36]=[C:18]2[N:17]=1
Reactant: CC1CCNCC1
Reactant: Fc1ccc(C(F)(F)F)c(-c2c(Cl)nc3ncnn3c2Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(c2c(-c3cc(F)ccc3C(F)(F)F)c(Cl)nc3ncnn23)CC1
Yield: 57.9 %

Procedure:
A mixture of 4-methylpiperidine(1.42 mmoles), triethylamine (1.42 mmoles) and dichloromethane (10 ml) is added to a mixture of 5,7-dichloro-6-(5-fluoro-2-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-α]pyrimidine (1.42 mmol) and dichloromethane (30 ml) under stirring. The reaction mixture is stirred 48 hours at room temperature and subsequently washed with dilute hydrochloric acid (5%). The organic layer is separated, dried with anhydrous sodium sulfate and filtered. The filtrate is evaporated under reduced pressure to yield 0.34 g of white crystals having a melting point of 149° C.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:19])[CH2:16][CH2:17][NH2:18].C>>[C:2]1([C:1]23[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[N:18]2[CH2:17][CH2:16][CH2:15][NH:19]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN
Reactant: O=C(O)CCCC(=O)c1ccccc1
Product: O=C1CCCC2(c3ccccc3)NCCCN12

Procedure:
19.2 Parts of 4-benzoyl-butyric acid and 9 parts of 1,3-propanediamine are heated for 21/2 hours at 150°-160°. The reaction mixture is cooled to about 60°, extracted with hot ethyl acetate and the solution obtained is clarified over charcoal. On concentrating, the reaction product precipitates and is purified by recrystallisation from ethyl acetate. The melting point of the 9a-phenyl-octahydro-6H-pyrido[1,2-a]pyrimidin -6-one of the formula ##STR34## obtained is 142.5°. The following compound is obtained in an analogous manner:
Reaction SMILES: [OH:1][C@H:2]([CH2:45][O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1.[H-].[Na+].[CH3:55]I>O1CCCC1>[CH3:55][O:1][C@H:2]([CH2:45][O:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1
Reactant: CI
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC[C@H](O)COc4ccccc4)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC[C@@H](COc4ccccc4)OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.330 g of benzyl 4-[4-(2(R)-hydroxy-3-phenoxypropoxy)phenyl]-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 3.0 ml of tetrahydrofuran is cooled to 0° C. and admixed with stirring with 0.018 g of NaH dispersion (60%). The mixture is stirred at room temperature over 1.5 hours and subsequently admixed with 0.056 ml of methyl iodide. The reaction mixture is stirred for a further 2 hours, poured onto water (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:1 EtOAc-heptane); Rt=5.54.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH2:9]/[C:10](/[O:17]CC)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]#[CH:8].[Cl:20][CH:21]([CH2:24][CH3:25])[CH:22]=[O:23].P(O)(O)([O-])=O.[Na+]>CCCCCC.O1CCCC1.O>[O:17]=[C:10]([CH2:9][CH2:6][C:7]#[C:8][CH:22]([OH:23])[CH:21]([Cl:20])[CH2:24][CH3:25])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCC(Cl)C=O
Reactant: C#CCC/C(=C/C(=O)OCC)OCC
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CC(=O)CCC#CC(O)C(Cl)CC
Temperature: -60 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
42.2 ml of 1.4 N butyl lithium in hexane were added with stirring to a solution of 10 g of ethyl γ-propargyl-β-ethoxy-crotonate in 75 ml of tetrahydrofuran cooled to -60°C and after holding the mixture at the said temperature for 2 hours, 6.5 g of α-chlorobutyraldehyde were added thereto. The mixture was held at -60°C for 1 hour and after raising the temperature to 0°C a mixture of 90 g of monosodium phosphate in 110 ml of water was added thereto. The mixture was decanted and the aqueous phase was extracted with ethyl acetate. The extracts were washed with a saturated sodium bicarbonate solution, then with water, was dried and evaporated to dryness. The oil residue was mixed with stirring with 120 ml of ethanol and 60 ml of 2 N hydrochloric acid for 16 hours and was then poured into water. The mixture was extracted with methylene chloride and the extracts were washed with water, dried and evaporated to dryness. The oily residue was chromatographed over silica and was eluted with a 3-1 cyclohexane-ethyl acetate mixture to obtain 5.8 g of ethyl 3-oxo-8-hydroxy -9-chloro-6-undecynoate with a refractive index of nD22 = 1.4855.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([S:6]([C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[C:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16]C[C:14]1=[O:20])=[O:12])(=[O:8])=[O:7])[CH3:5].C1(=O)NCCCC1>>[CH3:1][CH2:2][CH2:3][CH:4]([S:6]([C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[C:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][C:14]1=[O:20])=[O:12])(=[O:7])=[O:8])[CH3:5]
Reactant: CCCC(C)S(=O)(=O)c1ccccc1C(=O)N1CCCCCC1=O
Agent: O=C1CCCCN1
Product: CCCC(C)S(=O)(=O)c1ccccc1C(=O)N1CCCCC1=O

Procedure:
Synthesized as for N-[(4-pentylsulfonyl)benzoyl]caprolactam (Example V) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>COCCOC.O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8]
Reactant: Clc1ccccc1Br
Reactant: COc1cccc(Cl)c1B(O)O
Solvent: O
Solvent: COCCOC
Product: COc1cccc(Cl)c1-c1ccccc1Cl
Yield: 73.7 %

Procedure:
Treatment of 2-bromochlorobenzene (15.5 g, 80.6 mmol) with 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 5.0 g (74%) of 2.2′-dichloro-6-methoxybiphenyl as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([C:7]([N:9](C(=O)C2C=CC(OC)=CC=2)[C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:29]([CH3:31])[CH3:30])[CH:16]=3)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[K+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:29]([CH3:30])[CH3:31])[CH:16]=3)[N:11]=2)=[O:8])=[CH:42][CH:43]=1
Reactant: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3cccs3)c2C#N)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2nc3ccc(N(C)C)cc3c(NCc3cccs3)c2C#N)cc1

Procedure:
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-dimethylamino-4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)benzamide in 20 mL of acetonitrile, 5 ML of 1N methanolic potassium hydroxide solution is added. The reaction mixture is heated under reflux conditions for 10 minutes, 1.5 mL of glacial acetic acid is added to it, then it is neutralized with 15 mL of 1M sodium hydrogen carbonate solution. The precipitate is filtered off, the yellow crystalline material is recrystallized from the mixture of 5 ml of dimethylformamide and 40 mL of ethanol. After drying 1.15 g of the title compound is obtained, m.p.: 163° C.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.C([O-])(=O)C.[Na+].Br[CH2:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>C(#N)C.O.CO>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)=[CH:35][CH:34]=1)(=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccc(CNc2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 70 °C
Yield: 54.2 %

Procedure:
To a 1-liter 3-necked round-bottomed flask equipped with overhead stirrer, reflux condenser, dropping funnel and thermometer and containing a stirred slurry of 33.8 g (0.195 mole) of sulfanilic acid in 150 ml of warm (60° C.) water was added 55 g (0.404 mole) of sodium acetate trihydrate and 50 ml of acetonitrile. The resulting yellow solution was heated to 70° C. and a solution of 35 g (0.127 mole) of the 4-(bromomethyl)benzophenone prepared above in 80 ml of acetonitrile was added dropwise over 11/2 hrs. The resulting solution was then refluxed for 5 hrs. Approximately 75 ml of acetonitrile was then removed by distillation at the same time that a dropwise addition of 32 ml of conc. HCl (over a 20 minute period) was made. The mixture was then vacuum filtered at 80° C. which gave a pale yellow powder. The powder was then slurried in 250 ml of water for 15 minutes and again isolated by vacuum filtration. The resulting solids were reslurried in 250 ml of methanol and isolated by vacuum filtration which afforded 25.28 g (54.2%) of purified 4-(((4-benzoylphenyl)methyl)amino)benzenesulfonic acid as a pale yellow powder, which decomposed at 257°-259° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:12][NH:13][CH3:14])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH2:9][CH:10]=[CH2:11])[CH2:12][N:13]([CH3:14])[S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CC[C@H](CNC)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)S(=O)(=O)c1ccccc1)c1cccc(Cl)c1
Reaction time: 16 h
Yield: 103.2 %

Procedure:
A solution of 2.0 g (9.53 mmol) of (S)-4-(3-chorophenyl)-5-methylamino-1-pentene (prepared as described by J. Hale et al., Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) and 5.0 mL (28.6 mmol) of diisopropylethylamine (DIPEA) in 20 mL of methylene chloride was cooled in an ice/ethanol bath. To this was added 1.46 mL (11.4 mmol) of benzenesulfonyl chloride and after 5 min the ice bath was removed. After stirring for 16 h, the reaction mixture was diluted with methylene chloride and washed with water containing 20 mL of 2 N HCl. The aqueous layer was reextracted with methylene chloride and the organic layers were washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (FCC) eluting with 15% ethyl acetate/hexanes to afford 3.44 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 2.38 (p, J=8, 1H), 2.55 (m, 1H), 2.59 (s, 3H), 2.94 (m, 2H), 3.37 (m, 1H), 4.95 (m, 2H), 5.60 (m, 1H), 7.05-7.3 (m, 4H), 7.46 (m, 2H), 7.55 (m, 1H), 7.69 (dd, J=1.5 and 6, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)=[CH:5][CH:4]=1.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[N:16]([C:15]([CH3:14])=[N:19][CH:18]=3)[CH2:12][CH2:13][CH:11]=2)=[CH:7][CH:8]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(C(=O)C2CC2)cc1
Product: Cc1ncc2n1CCC=C2c1ccc(O)cc1
Temperature: 225 °C

Procedure:
25 g (0.14 mol) of cyclopropyl 4-methoxyphenyl ketone is combined with 50 g (0.61 mol) of 2-methylimidazole and heated to 225° C. under nitrogen for 16 hr. The reaction is extracted with sodium hydroxide solution and the extract neutralized with ammonium chloride. Recrystallization from methylene chloride/methanol (1:1) provides the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25]
Reactant: COc1ccc2c(c1)c(CCNC(C)=O)cn2S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCCc1cn(S(=O)(=O)c2ccccc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of the compound obtained in Step A are dissolved in 100 ml of dichloromethane. The reaction mixture is then cooled in an ice-bath, and 3.81 ml of boron tribromide are added dropwise. After stirring at room temperature for two hours, the reaction mixture is poured into 500 ml of water and ice. The precipitate that forms is filtered off, washed with water and oven-dried at 50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=1.[Br:24]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:24][C:11]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][C:10]=1[CH:22]=[O:23]
Reactant: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (330 mg) was dissolved in N,N-dimethylformamide (30 mL), N-bromosuccinimide (356 mg) was added and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 270 mg, 66%).
Reaction SMILES: C[O:2][C:3](=[O:63])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][N:31]([C:33]4[CH:38]=[CH:37][C:36]([C@H:39]5[CH2:56][C@@:54]6([CH3:55])[C@@H:50]([CH2:51][CH2:52][C@:53]6([OH:60])[C:57]#[C:58][CH3:59])[C@H:49]6[C:40]5=[C:41]5[C:46]([CH2:47][CH2:48]6)=[CH:45][C:44](=[O:61])[CH2:43][CH2:42]5)=[CH:35][CH:34]=4)[CH3:32])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:62])[CH2:10][CH2:9]1)[CH3:7].[OH-].[K+].Cl>CCO>[OH:62][C@@H:13]1[CH2:14][C@H:15]2[C@:20]([CH3:21])([CH2:19][CH2:18][C@H:17]([O:28][CH2:29][CH2:30][N:31]([C:33]3[CH:38]=[CH:37][C:36]([C@H:39]4[CH2:56][C@@:54]5([CH3:55])[C@@H:50]([CH2:51][CH2:52][C@:53]5([OH:60])[C:57]#[C:58][CH3:59])[C@H:49]5[C:40]4=[C:41]4[C:46]([CH2:47][CH2:48]5)=[CH:45][C:44](=[O:61])[CH2:43][CH2:42]4)=[CH:35][CH:34]=3)[CH3:32])[CH2:16]2)[C@@H:22]2[C@@H:12]1[C@H:11]1[C@:25]([CH3:26])([C@@H:24]([OH:27])[CH2:23]2)[C@@H:8]([C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:63])=[O:2])[CH2:9][CH2:10]1
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]45)cc3)C[C@@]21C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 5 °C
Reaction time: 17 h
Yield: 92.4 %

Procedure:
To a solution of the compound of Example 1I (17.28 g, 20.0 mmol, 91% chemical potency, therefore 15.72 g, 18.2 mmol) in EtOH (173 mL) at 5° C. was charged 3N KOH (33.3 mL, 100 mmol) at a rate to maintain an internal temperature <7° C. The reaction was stirred at 5° C. for 17 hour. The reaction mixture was neutralized with 3N HCl (33.3 mL, 100 mmol) while maintaining the internal temperature <10° C. (end pH was adjusted from 4.63 to 4.87 with 0.2 mL of 3N KOH). The reaction mixture crystallized after a few minutes post addition of 3N HCl. The reaction mixture was allowed to warm to ambient temperature, seeded (20 mg of seed crystals), warmed to 40° C. for 3 hours and slowly cooled back to ambient temperature stirred an additional 16 hours. The slurry was filtered, washed and dried to provide 14.30 g (92.4%) of the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.C([O-])(=O)C.[Ag+]>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][O:9][C:1](=[O:8])[CH3:2])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCOCCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 199.6 %

Procedure:
1-Benzoyloxy-2-chloromethoxyethane (2-benzoyloxyethoxymethyl chloride) (2.14 g) was dissolved in dry acetonitrile (30 ml) and silver acetate (1.67 g) was added. The mixture was stirred overnight at room temperature and then filtered thru Celite 545. The solvent was removed under reduced pressure (about 1 mm Hg), giving 2-acetoxymethoxyethyl benzoate (2.37 g) as a clear, light yellow oil. NMR and IR spectra were consistent with this structure.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[O:37]=[C:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:45][CH2:44][CH:43]([N:39]4[CH2:40][CH2:41][CH2:42][C:38]4=[O:37])[CH2:48][CH2:47]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: O=C1CCCN1C1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 38.8 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (47.6 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (38.0 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (23.1 mg, 39%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:7][N:6]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)C[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.8 %

Procedure:
To a solution of (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (Description 13) (100 mg, 0.456 mmol) in DMF (10 ml) was added 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (143 mg, 0.547 mmol). Finally DIPEA (0.239 ml, 1.368 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Solvent was removed by evaporation, the residue was dissolved in ethyl acetate and the solution extracted with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness and the residue was purified by MDAP to yield the title compound (32 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[S:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:14]2[CH2:15][CH2:16][S:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[CH3:10]
Reactant: OC1CCSCC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCSCC2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (0.201 g, 1.00 mmol), tetrahydro-2H-thiopyran-4-ol (0.130 g, 1.10 mmol) and triphenylphosphine (0.341 g, 1.30 mmol) in tetrahydrofuran (5 mL) was added diethyl azodicarboxylate (40% solution in toluene, 0.591 mL, 1.30 mmol), and the mixture was stirred at room temperature for 1.5 hr. Tetrahydro-2H-thiopyran-4-ol (0.0591 g, 0.500 mmol), triphenylphosphine (0.157 g, 0.600 mmol) and diethyl azodicarboxylate (40% solution in toluene, 0.272 mL, 0.600 mmol) were added, and the mixture was further stirred for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (0.261 g, yield 86%) as colorless crystals.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](C(OC)=O)=[CH:16][C:15]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[N:14]2)=[CH:9][CH:8]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][C:15]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)Nc1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)Nc1ccn(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Yield: 191.9 %

Procedure:
To a solution of (2′-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl)amine (0.90 g, 2.95 mmol) in 20 mL of methylene chloride at ambient temperature was added trimethylaluminum (8.85 mL of a 2.0 M solution in toluene, 17.68 mmol) dropwise. The resulting solution was allowed to stir until no more gas evolution was observed (˜15 min). To this solution was added 1-[(4-methoxy)phenyl]-3-(methoxycarbonylamino)-5-(methoxycarbonyl)pyrazole (0.90 g, 2.95 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40° C. for 16 h and then was cooled to ambient temperature and quenched by the addition of saturated aq NH4Cl. After diluting with ethyl acetate, the organic layer was washed with 10% aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The solid residue was recrystallized from hexanes/ethyl acetate to afford 1.4 g (82%) of the title compound. LRMS (ES+): 577.9 (M+H)+.