Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH2:43])[N:33]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH:43][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:33]=1
Reactant: N#Cc1ccc(NCCN)nc1N
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 30 mg (0.14 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 45 mg (68% of theory) of the product as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([C:34](=[O:36])[CH3:35])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.080 g, 0.20 mmol) and triethylamine (0.059 ml, 0.42 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.016 ml, 0.22 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.062 g, 77%) as white solid. MS m/e: 403 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.N1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(CCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(CCc4ccc(-c5nnn[nH]5)cc4)cc3)ccc2c1
Temperature: 110 °C

Procedure:
A mixture of 0.35 g (0.96 mmol) of 4-(4-(2-quinolinylmethyloxy)phenethyl)benzonitrile, 0.31 g (4.8 mmol, 5 equiv.) of sodium azide, and 0.55 g (4.8 mmol, 5 equiv.) of pyridine hydrochloride in 15 ml of DMF are heated at 110° C. for 48 hours. The mixture is poured into ice water and the precipitate that forms filtered off and recrystallized from methanol-water to obtain 5-(4-(4-(2-quinolinylmethyloxy) phenethyl)phenyl)tetrazole. (M.P. 203° C.-206° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][C:13]#N)[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1.CC(C[AlH]CC(C)C)C.[OH2:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][CH:13]=[O:32])[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1
Reactant: O
Reactant: N#CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: -78 °C
Yield: 66 %

Procedure:
A solution of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetonitrile (300 mg, 0.78 mmol) in DCM (6 mL) was stirred at −78° C. for 10 minutes. Then DIBAL-H (1 ml, 1 mmol) was added slowly to the reaction mixture at −78° C. Then the mixture was heated at −78° C. for 2 hours. The mixture was diluted with water (30 mL) and extracted with EA (20 mL×3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by column (PE:EA=3:1) to afford the desired product of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetaldehyde (200 mg, yield: 66%). 1H-NMR (CDCl3, 400 MHz) δ 9.63 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.34 (d, J=9.8 Hz, 1H), 7.11˜7.13 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.75 (t, J=8.0 Hz, 1H), 3.42 (s, 1H), 3.03 (d, J=8.4 Hz, 1H), 2.61˜2.70 (m, 2H). MS (M+H)+: 315/317.
Reaction SMILES: C1COCC1.ClC1C=C2C(C=CN2)=CC=1F.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][NH:24]2)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].B.N1C=CC=CC=1>>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc2c(cc1Cl)NCC2
Agent: B
Agent: Fc1cc2cc[nH]c2cc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2cc[nH]c2cc1Cl

Procedure:
This material was produced from 6-chloro-5-nitro-oxindole (1 eq) and BH3 /THF (6 mol eq.) utilizing a method analogous to that described for 6-chloro-5-fluoro-indole (Preparation 29) in 99% yield (contaminated with some 6-chloro-5-nitro-indoline) and used directly in the subsequent borane/pyridine reduction.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[N:29][C:30]=1[F:31]>O>[Cl:24][C:25]1[C:30]([F:31])=[N:29][CH:28]=[C:27]([O:32][CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[CH:26]=1
Reactant: Oc1cnc(F)c(Cl)c1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ncc(OCCCOC2CCCCO2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
2-(3-Bromopropoxy)tetrahydro-2H-pyran (12.93 g, 57.9 mmol) and cesium carbonate (39.5 g, 121.0 mmol) were added to an N,N-dimethylacetamide solution (80 ml) of 5-chloro-6-fluoropyridin-3-ol (8.14 g, 55.2 mmol), and stirred overnight under a nitrogen atmosphere at 100° C. The reaction solution was cooled with ice, water was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Moritex NH, hexane:ethyl acetate=18:1 to 11:1) to obtain 3-chloro-2-fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (10.84 g, yield: 68%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:26][CH2:27][CH2:28][Cl:29].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([CH2:26][CH2:27][CH2:28][Cl:29])[C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1
Reactant: O=C1Nc2c(ccc3ccccc23)SC1c1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c2N1CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one (10.0 g) and 96% sodium hydroxide (1.96 g) in dimethylsulfoxide (150 ml) is added 1-bromo-3-chloropropane (6.78 g) under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed and distilled to remove the solvent. The residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1) and further is recrystallized from methanol to give 3-(4-chlorophenyl)-1-(3-chloropropyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3-H)-one (8.04 g). M.p. 110°-112.5° C.
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([OH:33])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([O:33][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC/C=C\C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h

Procedure:
Pivaloyloxymethyl iodide (162 mg, 0.67 mmole) was added at 0° C. to a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (197 mg, 0.45 mmole) and K2CO3 (93 mg, 0.67 mmole) in DMF (4 ml). The mixture was stirred at 0°-5° C. for 1 hour and diluted with ethyl acetate (30 ml). The dilute was washed with water and a saturated NaCl solution, dried over anhydrous MgSO4 and evaporated in vacuo. The residue was chromatographed on a silica gel column (5 g) with 1% methanol in CHCl3. The desired fractions were combined and concentrated in vacuo. The residue was dissolved in dioxane and lyophilized to afford 242 mg (97%) of the dioxane solvate of the title compound. Silica gel TLC: Rf 0.25 (1:1 CHCl3 -ethyl acetate). Estimated purity 85% (by HPLC). Mp. 90°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: CC1CO1
Reactant: FC(F)(F)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-3-(trifluoromethyl)benzene (1.0 g, 5.5 mmol) in THF (10.0 mL) was added 2.5 M of n-BuLi in hexane (2.2 mL) at −78° C. and stirred for 1 h. Propylene oxide (370 mg, 6.4 mmol) was added to the reaction mixture at −78° C. and slowly warmed to rt. The reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.33 (d, J=6.1 Hz, 3H), 1.40 (d, J=6.3 Hz, 1H), 3.08-3.22 (m, 2H), 4.21-4.33 (m, 1H), 7.29-7.34 (m, 1H), 7.58-7.64 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH2:23][CH2:22][CH2:21][CH2:20]1.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1OCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 273 mg of 2-(2-pyrrolidin-1-yl-ethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 2 hours, and then concentrated under reduced pressure.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]=1[C:18](=O)[CH3:19].[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>CO>[CH3:14][O:13][C:11]1[CH:12]=[C:7]2[C:8]([CH:18]=[CH:19][C:25]3([O:6]2)[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: CN1CCC(=O)CC1
Reactant: COc1cc(O)c(C(C)=O)cc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCNC1
Product: COc1cc2c(cc1[N+](=O)[O-])C=CC1(CCN(C)CC1)O2
Temperature: 50 °C
Yield: 68.3 %

Procedure:
Pyrrolidine (1.15 mL, 13.8 mmol) was added to 1-(2-Hydroxy-4-methoxy-5-nitro-phenyl)-ethanone (2.57 g, 12.2 mmol) (Banks, C. K.; Hamilton, C. S. J. Am. Chem. Soc. 1938, 60, 1370) and 1-Methyl-piperidin-4-one (1.60 mL, 13.0 mmol) in Methanol (50.0 mL) and the reaction was stirred under an atmosphere of nitrogen. After overnight stirring, ˜50% conversion was achieved. The mixture was heated at 50° C. for 30 h. Following basic workup, the crude material was purified on ISCO (0-12% MeOH:DCM) to afford 7-methoxy-1′-methyl-6-nitrospiro[chromene-2,4′-piperidin]-4-((3H)-one (2.42 g; Yield=64.9%).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:26](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:26]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: NC=O
Reactant: CC(C)COc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CC(C)COc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 1 reaction of 4,5-diamino-2-(2-isobutoxyphenyl)pyrimidin-6-one sulphate (1.4 g) with formamide (5 ml) afforded the title compound, 0.24 g, m.p. 272°-273° C., (recrystallised from ethanol).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=2)[CH2:10]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl dihydrochloride (0.596 g, 2.64 mmol,) in acetonitrile (25 mL) was added 2-chloro-5-nitro-6-picoline (0.685 g, 3.96 mmol,) and powdered potassium carbonate (1.45 g, 10.6 mmol), then heated to 65° C. for 4.0 hr, then at 45° C. for 16 hr. The reaction mixture was then allowed to cool to room temperature and filtered through a 10.0 g Varian Bond Elut SCX (stong cation-exchange) cartridge eluting with 50 mL of (1:1) methanol in dichloromethane, 25 mL of methanol, followed by 7N ammonia in methanol (50 mL). The filtrate was concentrated under vacuum, to afford 0.633 g (82%) of the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]=[CH:7][N:6]=1)=[O:4].[C:20](C1C=C(C(O[Si](C(C)(C)C)(C)C)C)C=CN=1)(=O)C>>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:20])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)ccn1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccnc(C(=O)CBr)c1

Procedure:
The title compound was prepared according to the procedure for preparing 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine described in Example 95 from 2-acetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][C:28]([C:30]1[C:35]([NH2:36])=[CH:34][C:33]2[O:37][CH2:38][O:39][C:32]=2[CH:31]=1)=[O:29]>O1CCCC1>[C:28]([C:30]1[C:35]([NH:36][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:34][C:33]2[O:37][CH2:38][O:39][C:32]=2[CH:31]=1)(=[O:29])[CH3:27]
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OCc2ccccc2)cc(C(=O)Nc2cc3c(cc2C(C)=O)OCO3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into solutions of 163 (2.77 g, 0.01 mmol) in 200 mL of dry tetrahydrofuran were added triethylamine (10 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (1.79 g, 0.01 mmol). The mixtures were stirred at room temperature for 24 h and then evaporated. The residue was purified by column chromatography (SiO2, CH2Cl2/EtOAc=3/1) to give 164.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O>[CH3:22][S:23]([O:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(OS(C)(=O)=O)c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
tert-Butyl 4-(hydroxy(pyridin-2-yl)methyl)piperidine-1-carboxylate (Prepared in Example 124; 8.00 g, 27.4 mmol) and TEA (11.4 ml, 82.1 mmol) were combined and cooled to 0° C. Methanesulfonyl chloride (2.65 ml, 34.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 hours. Water was added and the reaction mixture was extracted with dichloromethane. The organic layer was dried, filtered, and concentrated to give tert-butyl 4-((methylsulfonyloxy)(pyridin-2-yl)methyl)piperidine-1-carboxylate (9.9 g, 97.7% yield). 1H NMR (DMSO-d6) δ 10.88 (bs, 1H), 8.49 (d, 1H), 8.35 (d, 1H), 7.95 (m, 1H), 7.75 (s, 1H), 7.65 (t, 1H), 7.57 (d, 2H), 7.42 (m, 3H), 7.36 (m, 1H), 7.31 (s, 1H), 7.21 (m, 1H), 7.14 (d, 1H), 5.23 (s, 2H), 4.19 (d, 1H), 3.98 (m, 1H), 3.84 (m, 1H), 2.14 (m, 2H), 1.37 (m, 10H), 1.20 (m, 3H), 1.01 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[C:20]([CH3:37])=[N:21][C:22]([CH:25]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:26]4)=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:38])[O:4][N:3]=1.[CH3:39][C:40](N=C(N(C)C)N(C)C)([CH3:42])[CH3:41].BrCC(C)C>C(#N)C>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:25]([C:22]2[N:21]=[C:20]([CH3:37])[C:19]([N:18]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:38])=[CH:14][CH:13]=3)(=[O:16])=[O:17])=[CH:24][CH:23]=2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 80 °C
Yield: 48.9 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-{2-methyl-6-[1-(phenylmethyl)-3-pyrrolidinyl]-3-pyridinyl}benzenesulfonamide (211 mg, 0.396 mmol) and N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (67.9 mg, 0.396 mmol) in acetonitrile (3 mL) was added 1-bromo-2-methylpropane (0.086 mL, 0.792 mmol). The reaction vessel was sealed and heated at 80° C. for 8 hours. The reaction mixture was separated between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with brine and dried over magnesium sulphate. The solvent was removed in vacuo. The sample was purified by flash silica (Si) chromatography (0-25% methanol-dichloromethane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product (114 mg) as a brown gum. LCMS (2 min, formic) Rt 1.01 min, m/z (ES+) 589 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH2:20])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])O.[Na+]>O1CCCC1.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH:20][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1)Oc1ccccc1
Yield: 94.7 %

Procedure:
A solution of 2 g of 2-amino-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate, 3.34 g of phenyl chloroformate, 1.79 g of sodium hydrogen carbonate in 40 cm3 of tetrahydrofuran and 4 cm3 of water is stirred for about 60 hours at a temperature in the region of 20° C. After concentrating the reaction mixture to dryness, the residue is taken up in 20 cm3 of water. The solid is filtered off by suction and washed with twice 5 cm3 of water, and then dried in an oven at 50° C. 2.5 g of 2-[(phenoxycarbonyl)amino]-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate are thus obtained in the form of a brown solid, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20].CN(C=O)C>O>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:19][CH3:20]
Reactant: CCI
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a 500 ml three-neck flask equipped with a mechanical stirrer and an inert gas tube were added 30.5 g of isovanillin, 55.2 g of potassium carbonate, 49.9 g of iodoethane and 140 ml of DMF. The mixture was stirred overnight at the room temperature. The mixture was poured into 1400 ml of water, and then the resultant mixture was extracted with ethyl acetate (600 ml×2). The ethyl acetate layers were combined. The organic phase was washed with saturated Na2CO3 (200 ml×3), 200 ml of water and 200 ml saturated NaCl, dried over anhydrous MgSO4, and filtered. The solvent was evaporated to give a straw yellow solid. The solid was recrystallized with a mixed solvent of ethyl acetate and petroleum ether (1:4) to give a white needle crystal (32.9 g). MS (m/z): 181 [M+1]+.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:17])[CH3:16])=O>>[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:1])([CH3:17])[CH3:16]
Reactant: [Cl-]
Reactant: CC(C)c1ccccc1OC(=O)Cl
Agent: [Al+3]
Product: CC(C)c1ccccc1Cl
Temperature: 200 °C
Yield: 20 %

Procedure:
0.35 g of anhydrous aluminium chloride was added to 25 g of 2-isopropylphenyl chloroformate and the mixture was heated at 200° C. for 3 hours at normal pressure. The reaction mixture was cooled and worked up as described in Example 1. 2-Isopropylchlorobenzene was obtained in a yield of 20%, which is considerable despite the unfavourable substitution pattern.