Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].IC.[CH3:40]COC(C)=O>CN(C=O)C>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[N:27]([CH3:40])[CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1C#N
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1C#N
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 9.14 mg) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D9) (120 mg) in dry DMF (5 mL) at RT. After stirring for 5 min, iodomethane (0.032 mL) was added. The resulting solution was stirred at RT for 15 min, then 1 hour more. EtOAc (50 mL) was added and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (50 mL), followed by water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D10) (60 mg) as a pale yellow oil. MS (ES): C28H30N4O4 requires 486; found 487.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=N\C(=O)C)/[N:6]([CH:8]([F:10])[F:9])[CH:7]=1.[OH:15]S([O-])(=O)=O.[K+]>CC#N.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]([F:10])[F:9])[CH:7]=1
Reactant: CC(=O)/N=c1\ccc(Br)cn1C(F)F
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1ccc(Br)cn1C(F)F
Yield: 52 %

Procedure:
To a stirred solution of the crude N-[5-Bromo-1-difluoromethyl-1H-pyridin-(2E)-ylidene]-acetamide (1 g) in 10 ml CH3CN was added 1% KHSO4 in water (10 ml). The reaction mixture was heated at reflux for 3 hrs. The reaction mixture was cooled down and the solvent was removed under reduced pressure. Without any workup this crude was purified by column chromatography using 10% ethyl acetate in hexane to get 5-Bromo-1-difluoromethyl-1H-pyridin-2-one (550 mg, 52%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH3:9][C:7]1([CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3](=[O:18])[CH:2]([NH:1][C:19](=[O:21])[CH3:20])[CH2:8]1
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide was prepared from 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one and acetic anhydride in an analogous manner to Example 1271d as a white solid. (420 mg, 90%), HPLC 99% purity, HNMR (DMSO) 10.21 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 4.28-4.21 (m, 1H), 2.23-2.17 (m, 1H), 2.02-1.95 (m, 1H), 1.81 (s, 3H), 1.45 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: N(OCCC(C)C)=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:42]=[CH:43][CH:44]=1)[O:20][C:21]1[CH:27]=[C:26]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]([CH3:39])[C:29]2=[O:40])[C:25]([F:41])=[CH:24][C:22]=1N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:22]1[CH:24]=[C:25]([F:41])[C:26]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]([CH3:39])[C:29]2=[O:40])=[CH:27][C:21]=1[O:20][C:19]1[CH:18]=[C:17]([CH:44]=[CH:43][CH:42]=1)[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(N)cc2F)c1=O
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
0.34 g of isoamyl nitrite was added dropwise to a mixture of 1.5 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 0.57 g of copper (I) chloride, 1.17 g of copper (II) chloride, and 21 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.01 g of ([3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:32][C@H:33]4[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]4)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (3.5 g, 7.5 mmol) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol) in DMF (32 mL) was added diisopropylethylamine (2.6 mL, 15.1 mmol). The reaction mixture was heated at 90° C. for 75 minutes. The mixture was cooled to room temp and diluted into aqueous saturated NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine (3 times), dried (MgSO4), filtered and concentrated under vacuo. The resulting residue was purified via silica gel chromatography (0%-10% MeOH/CH2Cl2) to afford the desired product 1b as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[N:4]=1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:27]=[CH:26]2>O1CCOCC1.ClCCl.CN(C)C1C=CN=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[N:4]=[C:3]([CH3:2])[O:7][N:6]=4)=[CH:9][CH:10]=3)=[O:15])[CH2:17][CH2:18]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: Cc1nc(-c2ccc(C(=O)N3CCNCC3)cc2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The BOC group is cleaved off using 4N HCl in dioxane. A solution of 100 mg of the resulting [4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]piperazin-1-ylmethanone (“A”) and 120 mg of 6-chloronaphthalene-2-sulphonyl chloride in 5 ml of dichloromethane is admixed with 400 mg of 4-dimethylaminopyridine on polystyrene, and the mixture is stirred at room temperature For 18 hours. Filtration and removal of the solvent gives [4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl][4-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]methanone, FAB 497.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([B:16]([OH:21])[OH:17])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1cccc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OB(O)c1cc2cccc(Cl)c2s1
Temperature: -30 °C
Yield: 96.2 %

Procedure:
To a solution of 7-chlorobenzo[b]thiophene (1.0 g, 5.92 mmol) in THF (25 mL) at −78° C. was added “butyllithium (7.41 mL, 11.8 mmol, 1.6 M solution). The reaction was allowed to warm to −30° C. then was cooled back to −78° C. and triisopropyl borate (2.23 g, 11.8 mmol) was added. The mixture was allowed to warm to 0° C., saturated ammonium chloride added and the organic phase separated off and concentrated in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) and the mixture was washed with DCM. The aqueous phase was acidified with 2N sulfuric acid, and the resulting precipitate isolated by filtration and dried under vacuum to yield 7-chlorobenzo[b]thiophene-2-boronic acid (1.21 g, 96%) as white solid. 1H NMR (400 MHz, CDCl3) δ=7.41 (t, J=7.70 Hz, 1H), 7.50 (d, J=7.70 Hz, 1H), 7.91 (d, J=7.70 Hz, 1H), 8.03 (s, 1H), 8.63 (s, 2H); MS (ES+): m/z 211.86 [M+].
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CN(C)C=O>[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])=[CH:19][CH:18]=1
Reactant: NCc1ccc(N)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (406 mg, 2.0 mmol) in N,N-dimethylformamide (250 μL) is added 4-aminobenzylamine (244 mg, 2.0 mmol). The reaction mixture is shaken at ambient temperature for 1.5 hours, then concentrated. Ethyl acetate is added to the solid residue that remained and the solid is recovered by filtration, rinsing with diethyl ether, and drying to yield 555.5 mg of 4-[(4-Amino-benzylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[CH3:24][O:25][CH2:26][CH2:27][C:28]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:33]([C:28]1([CH2:27][CH2:26][O:25][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:34]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Reactant: COCCC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(C)c3=O)cc2)C(=O)OC)CCCC1
Yield: 59.4 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (47.4 mg, 0.25 mmol), 1-(2-methoxyethyl)cyclopentane carboxylic acid (47 mg, 0.28 mmol), DIEA (175 μL, 1.0 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with ethyl acetate to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (70.5 mg, 59%). LR-Electrospray: m/z positive ion, 943 (2M+Na), 483 (M+Na), 478, (M+NH4), 461 (M+H); negative ion 919 (2M-H), 521, 459 (M−H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>C1COCC1>[C:15]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])(=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)Cl
Reactant: OCCOCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOCCO
Reaction time: 2 h
Yield: 48.9 %

Procedure:
25 g (0.235 mol) of diethylene glycol was dissolved in 150 mL of THF. 18 mL of (0.13 mol) of triethyl amine was added, followed by the dropwise addition of 10.8 g (8 mL, 0.12 mol) of acryloyl chloride. The reaction temperature was kept below 30° C. The reaction was allowed to continue for 2 hours at room temperature. The precipitated triethyl amine hydrochloride was removed by filtration, 100 mg BHT was added and the solvent was removed under reduced pressure. Diethylene glycol monoacrylate was purified on a Prochrom LC80-system, using Kromasil 60A 10 μm spherical silica. Methylene chloride/ethyl acetate 60/40 was used as eluent at a flow rate of 200 mL/min. 10 mg BHT was added before evaporation of the eluent. 9.4 g of diethylene glycol monoacrylate was isolated.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>C(O)C>[Cl:7][CH2:8][C@@H:9]([OH:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C[C@H](O)CCl

Procedure:
In a stainless steel autoclave, 21 mg of sodium carbonate and 14.1 mg (0.008 mmol) of Ru2Cl4 ((-)-BIFLUP)2NEt3 were charged, and the air in the autoclave was replaced with nitrogen. Further, 6.6 ml of ethanol and 2.7 ml (20 mmol) of ethyl 4-chloroacetoacetate were added, and the nitrogen in the autoclave was replaced with hydrogen. At a hydrogen pressure of 10 kgf/cm2, the solution was stirred for 2 hours at 100° C. After termination of the reaction, the conversion ratio, selectivity and optical purity were measured by gas chromatography and liquid chromatography. At a conversion ratio of 100%, selectivity of 96.3% and optical purity of 96.8%ee, ethyl 4-chloro-(S)-3-hydroxybutyrate was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21]1(OCC[O:24]1)[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12]([OH:15])[CH2:13][S:14][C@H:9]12)=[O:6]>C(O)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12]([OH:15])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C1(CBr)OCCO1
Solvent: CC(=O)O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 66.2 %

Procedure:
7-[2-Methoxyimino-3,3-ethylenedioxy-4-bromobutyramido]-3-hydroxycepham-4-carboxylic acid (syn isomer, 1 g.), 70% aqueous hydroperchloric acid (0.2 ml.) and acetic acid (2 ml.) were treated in a similar manner to that of Example 10 (4) to give 7-[2-methoxyimino-3-oxo-4-bromobutyramido]-3-hydroxycepham-4-carboxylic acid (syn isomer, 0.6 g.).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C(Cl)Cl>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:4][OH:3])[CH2:11][CH2:10]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of the above ester (1.29 g, 4.79 mmol) in CH2Cl2 (20 mL) at 0° C. was added a solution of LiAlH4 in THF (1.0 M, 13.9 mL, 13.87 mmol) and the mixture was heated to reflux. After 1 h, the mixture was cooled back down to 0° C. and quenched with H2O (0.51 mL), 15% NaOH (0.51 mL), and H2O (1.53 mL). After stirring for 30 min, the reaction mixture was dried (MgSO4), filtered, and concentrated to afford [1-(toluene-4-sulfonyl)-piperidin-4-yl]-methanol as a clear oil (1.24 g, 100%). 1H NMR (CDCl3) δ 1.31-1.43 (m, 4H), 1.79 (d, 2H, J=12.0 Hz), 2.24 (t, 2H, J=12.0 Hz), 2.43 (s, 3H), 3.47 (d, 2H, J=6.0 Hz), 3.81 (d, 2H, J=12.0 Hz), 7.32 (d, 2H, J=6.0 Hz), 7.64 (d, 2H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:30][C:31]([F:54])([F:53])[C:32]1[CH:52]=[CH:51][C:35]([CH2:36][C@H:37]2[CH2:41]OS(=O)(=O)[N:38]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:34][CH:33]=1.Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:41][C@@H:37]([NH:38][C:44](=[O:45])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:36][C:35]3[CH:51]=[CH:52][C:32]([C:31]([F:54])([F:53])[F:30])=[CH:33][CH:34]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-ylcarbamate (0.587 g, 1.72 mmol) and cesium carbonate (1.12 g, 3.45 mmol) were heated to 50° C. in 15 mL THF in a round bottle flask. (S)-tert-Butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (0.855 g, 2.24 mmol) in 10 mL THF was added to the flask dropwise, and the mixture was heated at 50° C. for 30 minutes. The flask was then cooled to 20° C., and 10 mL 1 N HCl was added to the flask. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was combined with 200 mL EtOAc. The organic phase was washed with water, twice with saturated ammonium sulfate, and dried over sodium sulfate. After removing the solvent, the product was obtained as yellow oil. LCMS indicated two major peaks with the same desired product M+1. The product thus obtained was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-hydroxyphenyl)butanol (125 g, 0.75 mole) in acetone 0.85.8 g (1.25 mole) anhydrous potassium carbonate (285.8 g, 1.25 mole) was added, followed by 160.8 (0.94 mole) benzyl bromide. The reaction mixture was then heated at reflux for 25 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake washed with acetone. The filtrate was concentrated to dryness. The solid residue was washed twice with 500 ml hexane. After drying under high vacuum overnight, 161 g of the desired product were obtained, which was homogeneous on TLC. The 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: Nc1cccnc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)Nc1cccnc1
Yield: 51 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 3-aminopyridine to give Compound 19 (0.18 g, 51%) as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:26]2[C:34]3[C:33](Cl)=[N:32][CH:31]=[N:30][C:29]=3[NH:28][CH:27]=2)O)=[CH:20][N:19]=1)[CH2:8][C:9]1[C:10]([O:16][CH3:17])=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=[O:40].C([SiH](CC)CC)C.C(#N)C>O>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][NH:7][C:18]2[N:19]=[CH:20][C:21]([CH2:24][C:26]3[C:34]4[C:33]([OH:40])=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[CH:22][CH:23]=2)[C:10]([O:16][CH3:17])=[N:11][CH:12]=1
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C(O)c2c[nH]c3ncnc(Cl)c23)cn1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CC#N
Product: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncnc(O)c23)cn1
Yield: 44 %

Procedure:
{5-[(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-pyridin-2-yl}-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (78, 0.022 g, 0.043 mmol), trifluoroacetic acid (0.062 mL, 0.80 mmol), triethylsilane (0.15 mL, 0.97 mmol) and 0.46 mL acetonitrile were combined in a round bottom flask. The reaction was heated at reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with methanol in dichloromethane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (P-0099, 0.0072 g). MS (ESI) [M+H+]+=380.8.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:31]([O:33][CH:34]=[CH2:35])=[O:32]>ClCCCl>[CH:34]([O:33][C:31]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:10][CH2:9]1)=[O:32])=[CH2:35]
Reactant: C(=C/C1CCN(Cc2ccccc2)CC1)\c1ccccc1OCC1CCCCC1
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)N1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
2.848 g of 1-benzyl-4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine was dissolved in 15 ml of 1,2-dichloroethane, 0.93 ml of vinyl chloroformate was added thereto, and the mixture was stirred at room temperature for 50 minutes and heated under reflux for one hour. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:1), to give 2.026 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:27])=[O:26]
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A stirred solution of 7-amino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mmol) and triethylamine (70 μl; 0.5 mmol) in THF (1 ml) was added a solution of CH3SO2Cl (40 μl; 0.5 mmol) in THF (1 ml) and stirred at rt. over night. The reaction mixture was evaporated to dryness, suspended in H2O and extracted by EtOAc. The combined organic fractions were evaporated to dryness. Column chromatography gave 40 mg product. M.p. 177–180° C.