Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].Br[CH:16]([CH2:21][CH2:22][CH2:23][Br:24])[C:17]([O:19][CH3:20])=[O:18]>>[Br:24][CH2:23][CH2:22][CH2:21][CH:16]([O:14][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]=1[N+:1]([O-:3])=[O:2])[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Reactant: COC(=O)C(Br)CCCBr
Product: COC(=O)C(CCCBr)Oc1ccc2c(c1[N+](=O)[O-])CCCC2

Procedure:
In a manner similar to that of Reference Example 5, 5,6,7,8-tetrahydro-1-nitro-2-naphthol was allowed to react with methyl 2,5-dibromovalerate to give methyl 5-bromo-2(5,6,7,8-tetrahydro-1-nitro-2-naphthyloxy)valerate, which was then allowed to react, in a manner similar to that of Reference Example 8, with 1-(4-fluorophenyl)piperazine to obtain methyl 5-[4-(4-fluorophenyl)-1-piperazinyl]-2-(5,6,7,8-tetrahydro-1-nitro-2-naphthyloxy)valerate as an oily product. The overall yield was 65.1%. NMR(CDCl3)δ: 1.55-2.17(8H,m), 2,41(2H,5,J=7.2 Hz), 2.52-2.81(8H,m), 2.96-3.14(4H,m), 3.72(3H,s), 4.67(1H,t,J=6 Hz), 6.55-7.11 (6H,m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:26][C:27]1([CH3:34])[CH:32]([OH:33])[CH2:31][CH2:30][NH:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:29]3[CH2:30][CH2:31][C@H:32]([OH:33])[C:27]([CH3:34])([CH3:26])[CH2:28]3)=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1(C)CNCCC1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
General synthesis of amides: A 10 mL scintillation vial was charged with the 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol (0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2 mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to 70° C. and stirred for 2 h. After cooled to room temperature, the mixture was purified via preparative HPLC and dried (lyophilizer) to afford (S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl) benzenesulfonamide (1:2 mixture of rotamers): 1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.54 (s, 1 H), 8.26 (d, 1 H), 8.12 (d, 1 H), 8.00 (d, 1 H), 7.88 (dd, 1 H), 7.62 (d, 1 H), 4.05 (m, 1 H), 3.70 (d, 1 H), 3.50 (m, 2H), 3.40 (m, 1 H), 3.10 (d, 1 H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H); MS (ES) (M+H)+ expected 526.0, found 526.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[N:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[N:16][CH:15]=[CH:14][C:11]=1[C:12]1[NH:22][N:21]=[N:20][N:13]=1
Reactant: N#Cc1ccncc1Nc1ccc(I)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnn[nH]1
Temperature: 100 °C

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]isonicotinonitrile (100 mg, 0.29 mmol), ammonium chloride (28 mg, 0.52 mmol), and sodium azide (35 mg, 0.54 mmol) were dispended into a seal tube equipped with a stirring bar. The seal tube was degassed by vacuum and recharging with nitrogen three times before addition of anhydrous DMF (3 mL). The mixture was heated at 100° C. for three days. The mixture was diluted with saturated NaHCO3 and washed with EtOAc. The aqueous phase was acidified with concentrated HCl to pH<1, and washed with EtOAc. The aqueous layer was dried to give the desired product. LC/MS [Method B: rt: 6.008 min; m/z: 383 (M+1)].
Reaction SMILES: [CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(Cl)Cl.ClC(OCC)=O.[NH3:29]>C(N(CC)CC)C>[CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([NH2:29])=[O:18])=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1OCc2cc(C(=O)O)ccc2O1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCC1OCc2cc(C(N)=O)ccc2O1
Temperature: 0 °C

Procedure:
A mixture of 3.0 g of 2-pentyl-1,3-benzodioxan-6-carboxylic acid (prepared in accordance with Example 12), 60 ml of chloroform and 2.2 ml of triethylamine is cooled to 0° C. 1.5 ml of ethyl chloroformate are added dropwise while stirring. The mixture is stirred at 0° C. for 1 hour and then ammonia gas is conducted in. The mixture is stirred at room temperature for 5 hours and then evaporated. The residue is stirred up with 100 ml of water and the suspension is suction filtered. The material on the suction filter is dried and boiled up with hexane. There is obtained 2-pentyl-1,3-benzodioxan-6-carboxamide as a beige powder; m.p. 162.5°-163° C.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1cccc(Cl)c1
Product: COC(=O)c1cc(Cl)ccc1COc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-chlorophenol:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](SC)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44][NH2:45])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44][NH:45][C:26]2[S:27][C:23](=[CH:22][C:20]3[CH:19]=[CH:18][C:4]([O:5][C:6]4[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=4[C:14]([F:17])([F:15])[F:16])=[C:3]([O:2][CH3:1])[CH:21]=3)[C:24](=[O:30])[N:25]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Product: COc1cc(C=C2SC(NCC3CN(C(=O)OC(C)(C)C)CCO3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
2-({5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester was prepared using 4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile and 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester as described in Example 5C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[CH:10][CH:9]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:29][CH2:30][C:31]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:20])([F:21])[CH:17]([F:18])[F:19])=[CH:10][CH:9]=1)=[O:32]
Reactant: CCOC(=O)CNc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)CCl)c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.1 g of the resulting N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline, 1.1 ml of triethylamine and 50 ml of dichloromethane was added dropwise a solution of 0.6 ml of chloroacetyl chloride in 6 ml of dichloromethane with ice cooling and the resulting mixture was stirred at room temperature for five hours. To the reaction solution was added 50 ml of dichloromethane and 100 ml of ice water to factionate. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane (1:2 v/v!) to give 2.4 g of N-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline as a yellow oily substance.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.Cl>CO>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(N)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
3,4-dimethoxy-3-cyclobutene-1,2-dione (428 mg) was added to a solution of N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]benzamide hydrochloride (555 mg) [prepared as described in step (d) above] in methanol (15 ml) at ambient temperature. After stirring for 10 minutes, a solution of triethylamine (153 mg) in methanol (10 ml) was added dropwise to the mixture. This mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then slightly acidified with hydrochloric acid (0.5N) and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford the title compound (505 mg) as a white foamy solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[C:4]([F:19])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][N:26]([C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[F:19])[CH:9]=1)[CH3:27])[CH3:22]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)c1cccc(COc2ccc(Br)cc2F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(Br)cc2F)c1

Procedure:
A solution of 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid (5.21 g, 16.02 mmol), N-methyl glycine ethyl ester hydrochloride (4.9 g, 32.05 mmol), DIEA (14 mL, 80.01 mmol), EDCI (6.1 g, 32.05 mmol) and HOAT (4.4 g, 32.05 mmol) in methylene chloride (300 mL) was stirred at room temperature for 12 h. The mixture was evaporated and the residue was purified by column (0-50% EtOAc in hexane) to give {{[3-(4-bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester, 4.5 g (66%). LC-MS (ES) calculated for C19H19BrFNO4, 423; found m/z 424 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Br:26])[C:23]([Cl:27])=[CH:22][C:21]=1[OH:28].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[O:28][C:21]1[CH:22]=[C:23]([Cl:27])[C:24]([Br:26])=[CH:25][C:20]=1[Cl:19]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Oc1ccccc1
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2cc(Cl)c(Br)cc2Cl)cc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 28.4 gm of 4,5-dichloro-2-nitro-1-phenoxy-benzene, 24.2 gm of 2,5-dichloro-4-bromo-phenol, 10 ml of 10 N sodium hydroxide and 80 ml of dimethylsulfoxide was stirred for 5 hours at 100° C. Thereafter, the reaction mixture was stirred into 700 ml of 1 N sodium hydroxide, the mixture was allowed to stand overnight at room temperature, the liquid phase was decanted, and the precipitated product was taken up in chloroform. The chloroform solution was washed with water, dried with sodium sulfate and evaporated, and the residue was recrystallized from a mixture of 200 ml ethanol and 2 ml dimethylformamide. 36.5 gm (75% of theory) of the light yellow crystalline title compound, m.p. 85° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1.[K].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1nc(C2CC2)c2cc(-c3cccc(Cl)c3)ccc2[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(-c4cccc(Cl)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-(3-chlorophenyl)-4-cyclopropyl-1H-quinazolin-2-one (0.5 g, 1.68 mmol) in anhydrous DMF was added potassium hexmethylsilyl amide (0.45 g, 2.1 mmol) at ambient temperature under nitrogen. The reaction mixture was stirred at ambient temperature for 30 minutes, treated with p-methoxy benzyl chloride (0.35 mL, 2.5 mmol), and heated at 55° C. for 5 hours. The mixture was then cooled to room temperature and quenched with a saturated aqueous ammoniun chloride solution (10 mL). Methylene chloride (50 mL) was added and organic layer was separated. The aqueous layer was extracted with methylene chloride (2×20 mL) and the combined organic layers were washed with brine and dried (MgSO4). After removal of solvent, the residue was separated on a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-1-(4-methoxybenzyl)-1H-quinazolin-2-one as an off-white solid: mp 173-174° C.; 1H-NMR (DMSO-d6) δ 8.65 (d, 1H, J=1.8 Hz), 8.10 (dd, 1H, J=8.9, 1.8 Hz), 7.93 (d, 1H, J=1.6 Hz), 7.79 (d, 1H, J=7.6 Hz), 7.53 (d, 2H, J=8.4 Hz), 7.46 (t, 1H, J=8.1 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.6 Hz), 5.41 (s, 2H), 3.73 (s, 3H), 3.18 (m, 1H), 1.18-1.27 (m, 4H); MS (CI) m/z 417([M+H]+, 100%); Anal. Calc. For C25H21ClN2O2; C, 72.02, H, 5.08, N, 6.72. Found: C, 71.88, H, 4.91, N, 6.70.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3[nH]2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Temperature: -42 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 113D (0.17 g, 0.636 mmol) in N,N-dimethylformamide (3.5 mL) was cooled to 0° C. in an ice bath, and sodium hydride (60% dispersion in mineral oil, 0.031 g, 0.776 mmol) was added. The reaction mixture was stirred 30 minutes, cooled to −42° C., and (2-(chloromethoxy)ethyl)trimethylsilane (0.146 mL, 0.827 mol) was added dropwise over 3 minutes. The reaction was stirred at −42° C. for 1 hour and was quenched with saturated aqueous ammonium chloride (3 mL). The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 25% ethyl acetae in hexane, to provide the title compound. MS ESI(+) m/z 397.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:17]2[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([Cl:12])[N:18]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: Cc1cc(Oc2ccc(C(C)(C)C)cc2)nc(Cl)n1
Yield: 51 %

Procedure:
Prepared in analogy to example 81a) from 4-t-butylphenol and 2,4-dichloro-6-methylpyrimidine in a yield of 51%. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.44 (d, 2H), 7.07 (d, 2H), 6.54 (s, 1H), 2.45 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1C(=O)N([Br:23])C(=O)C1.O>CN(C=O)C>[Br:23][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c3ccccc3c2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Methoxy-9H-carbazole (Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403-9410) (0.029 g, 0.147 mmol) was dissolved in dry DMF (0.28 mL) and NBS (0.026 g, 0.147 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 h under absence of light. The solution was poured into water (2 mL), filtered and washed with water. The title compound was isolated as a grey solid (0.033 g, 82%).
Reaction SMILES: [CH:1](=[N:8][C@H:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:25]([CH2:28][C:29](Cl)=[O:30])=[N+:26]=[N-:27]>C(Cl)Cl>[C:14]([O:13][C:11]([C@@H:9]([N:8]1[C@@H:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:28]([N:25]=[N+:26]=[N-:27])[C:29]1=[O:30])[CH3:10])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: C[C@H](N=Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@H](N=[N+]=[N-])[C@@H]1c1ccccc1
Reaction time: 14 h
Yield: 41.1 %

Procedure:
To 75 ml. of a solution of N-benzylidene-1(S)-t-butoxycarbonylethylamine (5.07 g., 21.7 mmol) and triethylamine (4.84 g., 47.8 mmol) in methylene chloride, there was gradually added dropwise 75 ml. of a solution of azidoacetyl chloride (5.19 g., 43.5 mmol) in methylene chloride at -78° C. After stirring at -78° C. to room temperature for 14 hours, the reaction mixture was washed with water and then with a saturated saline solution, followed by drying over anhydrous magnesium sulfate. After removal of the solvent by distillation, the residue was subjected to silica gel column chromatography, using hexane-ethyl acetate (3:1) as an eluent, to give 1-(1(S)-t-butoxycarbonylethyl)-3(S)-azido-4(R)-azetidin-2-one (2.68 g., yield: 39%) and 1-(1(S)-t-butoxycarbonylethyl)-3(R)-azido-4(S)-phenylazetidin-2-one (2.82 g., yield: 41%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]=[CH:27][N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=4)[CH:27]=[N:28][CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 5-hydroxymethyl-pyridine-2-carbonitrile from step 3 (37 mg, 0.28 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (150 mg, 0.28 mmol) in CH2Cl2 (1.38 ml) was added DIEA (106 μl, 0.61 mmol) followed immediately by the addition of Tf2O (70 μl, 0.41 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (1.38 ml) and heated to 60° C. for several hours. The MeOH was removed in vacuo and the residue treated with saturated NaHCO3 (2 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine (1×10 mL), dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.CN(C)C=O.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])([O-:26])=[O:25]
Reactant: C[C@H]1CCCCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 99.2 %

Procedure:
(S)-2-methylpiperidine (270 μl, 2.24 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (211 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, (S)-1-[2-nitro-4-(trifluoromethyl)phenyl]-2-methylpiperidine (286 mg, 99.2%) was yielded as an orange-colored oily material.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:9][CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Acryloyl chloride (86.9 g) was added dropwise with stirring to a solution of 4-chlorobenzylamine (135.8 g) and triethylamine (133.5 ml) in dichloromethane (500 ml) at -15 to -20° C., under nitrogen. After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture was washed with dilute aqueous sodium hydroxide solution and then with water. The dichloromethane solution was dried and evaporated under reduced pressure. The solid residue was recrystallised from ethyl acetate to give N-(4-chlorobenzyl)acrylamide, m.p. 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)=[N:6][CH:7]=1.C([OH:24])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)=[N+:6]([O-:24])[CH:7]=1
Reactant: CCO
Reactant: CC1(C)CC(c2ccc(Cl)cn2)c2cc(C#N)ccc2O1
Product: CC1(C)CC(c2ccc(Cl)c[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 39, from 4-(5-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile there was obtained 5-chloro-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 159°-161° C. (from ethanol).