Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[NH:12][S:13](=O)(=O)[C:9]3[C:10]=2[C:5]([CH:6]=[CH:7][CH:8]=3)=[CH:4][C:3]=1CC(O)C.[H-].[Na+].[Br:22][CH2:23][CH:24]([OH:27])[CH2:25]Br>CN(C)C=O>[Br:22][CH2:23][CH:24]([OH:27])[CH2:25][N:12]1[C:11]2[CH:2]=[CH:3][CH:4]=[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([C:10]=23)[S:13]1
Reactant: OC(CBr)CBr
Reactant: CC(O)Cc1cc2cccc3c2c(c1Br)NS3(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CBr)CN1Sc2cccc3cccc1c23
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
2-(3-Bromo-2-hydroxypropylnaphtho[1,8-cd]isothiazole 1,1-dioxide may be prepared in the following manner: a solution of naphtho[18-cd]isothiazole 1,1-dioxide (41 g) in dimethylformamde (1000 cc) is added over 2 hours under a current of argon to a suspension of sodium hydride (9.6 g) in a 50% dispersion in vaseline oil in dimethylformamide (100 cc), maintaining the temperature between 20 and 35° C. The reaction medium is stirred for 30 minutes at a temperature of about 20° C., then 1,3-dibromo-2-hydroxypropane (20.5 cc) in dimethylformamide (500 cc) is added over 10 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is concentrated to dryness at 70° C under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is purified by chromatography on a silica column, under a current of argon with a mixture of dichloromethane and methanol (95-5 vol) as eluant. 2-(3-Bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1, -dioxide (62.1 g) is obtained, in the form of a green oil which is used in the crude state in the subsequent synthesis.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH3:11])[CH2:7][N:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=O.[Li+].[BH4-]>C1COCC1>[CH2:15]([O:14][C:12]([N:6]1[CH2:7][C@H:8]([O:10][CH3:11])[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To 5 mL of anhydrous THF was added 1.50 g (5.62 mmol) of (2S,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester and the mix was cooled to 0° C. To reaction mixture was added 3.34 mL of LiBH4 (2.0 M in THF) drop-wise over 5 min and was then stirred for 2 h. The mixture was quenched with 1 mL of Sat. NaHCO3, diluted with 50 mL of EtOAc and washed with Sat. NaHCO3 (2×50 mL). The organic layer was dried over NaSO4 and concentrated to give an amber oil. Purification was accomplished through 50 mL of silica eluting with EtOAc/CH2Cl2 (7:3). The pure factions were combined, concentrated and subsequently put on the high vacuum for 24 h to give 1.3 g (92%) of (2S, 4R)-2-Hydroxymethyl-4-methoxy-pyrrolidine-1-carboxylic acid benzyl ester as clear oil. HPLC: Rt 3.41 min. (100% area). 1H NMR (CDCl3, 300 MHz) δ; 7.51-7.38 (5H, m), 5.24-5.00 (2H, m), 4.45-4.40 (1H, m), 4.23-4.18 (1H, m), 3.95-3.73 (3H, m), 3.51-3.42 (1H, m), 3.31 (3H, s), 2.22-2.14 (1H, m). LCMS (APCI) (M+H+) m/z: 266.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[Cl:11])[C:5](Cl)=[O:6].[N+:16](=[CH2:18])=[N-:17]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:18]=[N+:16]=[N-:17])[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[Cl:11]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)cc(Br)c1Cl
Reactant: C=[N+]=[N-]
Product: [N-]=[N+]=CC(=O)c1cc(Br)c(Cl)c(S(N)(=O)=O)c1

Procedure:
33 g of 3-bromo-4-chloro-5-sulfamoyl-benzoyl chloride were reacted in a manner analogous to the method described in Example 1 b) with diazomethane to yield the 3'-bromo-4'-chloro-5'-sulfamoyl-diazoacetophenone and worked up. M.p. 193° C (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:2].Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(NS(C)(=O)=O)cc3)C(=O)OCc3ccccc3)c2c1
Yield: 73 %

Procedure:
The reaction of (2-(3,5-dimethylphenyl)-3-{2-[4-(4-methanesulfonylaminophenyl)butylamino]ethyl}-1H-indol-5-yl)acetic acid ethyl ester with benzyl chloroformate was carried out according to the procedure of Example 14.1, Step 14.1C, to give the titled compound in 73% yield as a stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=710 (M+H).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=[O:29])[N:14]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[CH:22]=[CH:21][C:20]=1[Cl:28])[CH:15]1[CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([O:12][C:13]([N:14]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][O:27][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH:22]=[CH:21][C:20]=1[Cl:28])[CH:15]1[CH2:16][CH2:17]1)=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)ccc1Cl)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)c(CN(C(=O)OC(C)(C)C)C3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
Et3N (2.56 mL, 18.4 mmol) and DMAP (153 mg, 1.23 mmol) were added to a sol. of [2-chloro-5-(2-hydroxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (4.00 g, 12.3 mmol) in CH2Cl2 (110 mL) at 0° C. A sol. of p-toluenesulfonyl chloride (2.80 g, 14.7 mmol) in CH2Cl2 (18 mL) was added dropwise, and the mixture was stirred for 3 days while warming up to rt. The mixture was partitioned between CH2Cl2 and water, and the aq. layer was extracted with CH2Cl2 (3×). The combined org. layers were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 8:2) yielded the title compound (4.90 g, 83%). LC-MS: tR=1.13 min; ES+: 480.53.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CS(O[CH2:37][C:38]1[C:43]([Br:44])=[CH:42][N:41]=[C:40]([Cl:45])[CH:39]=1)(=O)=O>CN(C=O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:37][C:38]3[C:43]([Br:44])=[CH:42][N:41]=[C:40]([Cl:45])[CH:39]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)OCc1cc(Cl)ncc1Br
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(Cl)ncc1Br
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 4, 1.305 g, 4.17 mmol) in 30 mL of DMF was cooled to −20° C. NaHMDS (1.0 M, 4.17 ml, 4.17 mmol) was added and the reaction was stirred at −20° C. for 20 minutes. Next, a solution of (5-bromo-2-chloropyridin-4-yl)methyl methanesulfonate (INTERMEDIATE 28, 1.2522 g, 4.17 mmol) in 5 mL of DMF was added and the solution turned brown. The reaction was warmed to 0° C. by switching to an ice/water bath and the reaction stirred for an additional 30 minutes, at which time an LCMS aliquot confirmed the reaction was complete. It was quenched with aqueous NaHCO3. The reaction was extracted with ethyl acetate, then washed with aqueous NaHCO3 and brine, dried with Na2SO4, filtered and the filtrate was concentrated. The crude oil was purified by silica gel chromatography to give the titled compound as an off-white solid. 1H NMR (CDCl3, 500 MHz): δ 8.52 (s, 1H), 7.92 (s, 1H), 7.80 (s, 2H), 7.36 (s, 1H), 5.81 (d, 1H), 4.78 (d, 1H), 4.34 (d, 1H), 4.17 (m, 1H), 0.82 (d, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:14][C:15]([N:17]1[C:21]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[C:22]2=[O:39])[C:20](=[O:40])[NH:19][C:18]1=[O:41])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOCC>[CH2:7]([O:14][C:15]([N:17]1[C:21]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[C:22]2=[O:39])[C:20](=[O:40])[N:19]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:18]1=[O:41])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: O=C1NC(=O)C2(C(=O)N(Cc3ccc(Cl)c(Cl)c3)c3ccccc32)N1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)N1C(=O)N(C(=O)OCc2ccccc2)C2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 16 h
Yield: 61.9 %

Procedure:
Ethyl chloroformate (0.6 g.) was added slowly to a stirred mixture of 3-benzyloxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (2.55 g.) and sodium carbonate (2.0 g.) in 1,2-dimethoxyethane (60 ml.). The mixture was stirred for 16 hours and the solid then removed by filtration. The filtrate was evaporated to give an oil which solidified on treatment with a few drops of ether. This solid was recrystallised from ethyl acetate/petrol 60-80 to give 3-benzyloxycarbonyl-1-ethoxycarbonyl-1'(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.), m.p. 128°-131° C.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[OH:36][CH2:35][CH2:37][NH:38][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: NCCO
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCO)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
4-{5-[2-Chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 50 mg, 0.104 mmol) in ethanolamine (1.5 mL) was heated under microwave irradiation at 150° C. for 30 mins. The reaction mixture was partitioned between water and DCM and the organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in MeCN and then purified by preparative C18 HPLC, eluting with a gradient of 20-90% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:19][OH:20])[CH:3]=1
Reactant: NO
Reactant: O=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 38 mmol) in methanol (200 mL) was added hydroxylamine hydrochloride (13.5 g, 190 mmol) followed by the addition of a sodium hydroxide solution (7.8 g, 190 mmol in 50 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried (magnesium sulfate) to give 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g, 84%) as a white solid. 1H-NMR (DMSO-d6): δ 11.56 (s, 1H), 8.44 (d, 1H), 7.80 (m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); 19F-NMR (DMSO-d6): δ −113.44; MS m/265 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)#[CH:15]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:15]#[C:14][CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.348 g, 1.20 mmol) synthesized in Example B46, Step 2 in triethylamine (10 mL) was added with tert-butyl 4-ethynylpiperidine-1-carboxylate (Journal of Medicinal Chemistry, Vol. 47, p. 3111, 2004, 0.276 g, 1.32 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0842 g, 0.120 mmol) and copper(I) iodide (0.0229 g, 0.120 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethynyl]piperidine-1-carboxylate (0.245 g, 55%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:45])[C:18](=[O:44])[C:19]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=[CH:36][CH:35]=4)[CH:28]=[N:27][C:20]=3[N:21]([CH:24]3[CH2:26][CH2:25]3)[C:22]=2[N:23]=1>C(Cl)Cl.C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:45])[C:18](=[O:44])[C:19]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N+:37]([O-:9])=[CH:36][CH:35]=4)[CH:28]=[N:27][C:20]=3[N:21]([CH:24]3[CH2:26][CH2:25]3)[C:22]=2[N:23]=1
Reactant: CN1C(=O)c2cc(CCOc3ccnc4ccccc34)cnc2N(C2CC2)c2nc(Cl)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)c2cc(CCOc3cc[n+]([O-])c4ccccc34)cnc2N(C2CC2)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.3 %

Procedure:
Solid mCPBA (177 mg, 0.82 mmol) was added to a solution of 2-chloro-11-cyclopropyl-5,11-dihydro-5-methyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (143 mg, 0.30 mmol) in CH2Cl2 (3 mL) and THF (3 mL). The mixture was stirred at room temperature for 14 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), the solution was successively washed with aqueous 10% Na2S2O3 (3×10 mL), aqueous saturated NaHCO3 (3×10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was partially purified by flash chromatography (EtOAc:MeOH, 95:5 to CH2Cl2:MeOH, 9:1). The impure compound was further purified by reverse phase HPLC (CombiPrep ADS-AQ 50×20 mm, 5 μ, 120 A, 5-100% MeCN+0.10% TFA/water+0.10% TFA in 25 min). The pure fractions were treated with aqueous saturated NaHCO3, extracted with EtOAc and the solution was dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (28.3 mg, 19%) as a white solid: MS (ESI) m/z 488/490 (MH)+.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH2:37][CH3:38].CO>>[OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:37][CH3:38])=[O:24])=[CH:21][N:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nc1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
Methyl 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (150 mg, 0.307 mmol) was dissolved in NH2Me/MeOH (10 mL). The mixture was stirred at rt overnight. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl) ethyl)phenyl)-N-methylnicotinamide (54 mg, 36%). LC-MS Method 2 tR=1.117 min, m/z=430.1; 1H NMR (CD3OD) 0.93 (s, 3H), 1.27 (s, 3H), 1.59 (d, 3H), 2.16 (s, 2H), 2.22-2.37 (m, 1H), 2.41-2.60 (m, 2H), 2.99 (s, 3H), 3.11 (m, 1H), 5.60 (m, 1H), 7.12 (d, 1H), 7.29 (m, 5H), 7.80 (m, 2H), 8.01 (d, 1H), 8.41 (d, 1H), 9.03 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:4].CC(C)([O-])C.[K+]>C1COCC1>[O:4]=[C:3]1[NH:5][CH2:6][CH2:7][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[O:21][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCNC(=O)CCl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCNC(=O)CO2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-(2-(2-chloroacetamido)ethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step c) (0.3 g) in dry THF (18 mL) was added dropwise over 6 hours to a refluxing mixture of potassium tert-butoxide (1M in tert-butanol, 3 mL) and dry THF (60 mL). At the end of the addition the mixture was heated at reflux for a further 15 minutes and then cooled to room temperature. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. Tritruration with diethylether afforded the subtitled compound. Yield 0.117 g.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Li]CCCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1>C1COCC1>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: OCc1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccccc1C1(O)CCC2(CC1)OCCO2
Temperature: -4 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromobenzyl alcohol (3.0 g, 16 mmol) in THF (40 mL) cooled at −78° C. was added a 2.5 M solution of n-BuLi in hexanes (14.1 mL). The mixture was stirred at −4° C. for 1 hour and cooled back to −78° C. To it was added a solution of 1,4-cyclohexanedione mono-ethylene ketal (2.5 g, 16 mmol) in TIE (10 mL) over 15 minutes. Stirring was continued at −78° C. for 30 minutes and at −4° C. for 1 hour. The reaction was quenched by addition of a solution of NH4Cl in water. The resulting solution was extracted with EtOAc three times. The combined extract was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5% MeOH/CH2Cl2 provided the title compound. MS calculated (M+H)+265. Found 287 (M+Na)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[C:9]([C:11]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
A solution of LDA (107 ml, 214.01 mmol) was added to a stirred solution of tert-butyl 4-cyanopiperidine-1-carboxylate (30 g, 143 mmol) in THF (250 ml) at −78° C., under nitrogen. The resulting solution was stirred at −78° C. for 30 minutes. Ethyl chloroformate (16.37 ml, 171.2 mmol) was added. The resulting solution was stirred and allowed to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3 (250 ml), extracted with DCM, and the organic layer was washed with saturated brine (100 ml) then dried over MgSO4, filtered and evaporated to afford the crude material as a orange oil. This material was purified by flash silica chromatography, elution gradient 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-tert-butyl 4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (20.8 g, 51.6%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:9][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1nc(Cl)c(Cl)nc1N
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccccc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g0 and 2-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.096 g.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24](=[O:27])([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:24](=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 4-trifluorobenzoyl chloride (96 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (129 mg, 62%).