Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.[F:26][C:27](S(=O)(=O)C1C=CC=CC=1)=[CH2:28]>C1(C)C=CC=CC=1.ClCCl>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:28]=[C:27]([F:26])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: C=C(F)S(=O)(=O)c1ccccc1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2cc(F)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.6 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)-oxazolidin-2-one (Reference Example 2) (0.7 g, 1.9 mmol) and (1-fluoroethenyl)-phenylsulfane dioxide (0.7 g, 3.8 mmol) (D. P. Mathews and J. R. McCarthy, JOC 55 (9), 1990, p 2973) were suspended/dissolved in toluene (5 ml) and heated to reflux under stirring for 2 days. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with phosphate buffer (pH 7) and dried over sodium sulfate. Chromatography on silica gel with hexanes/acetone (1:1) gave 28 mg (4%) of the title compound as a colourless solid (Rf ˜0.25, TLC:hexanes/acetone, 1:1). The major product was the corresponding 5-fluoro-1,2,3-triazoyl compound with an Rf of ˜0.2.
Reaction SMILES: C([Li])CCC.C1C2CC3C(=CC=CC=3)C=2C=CC=1.C(C(CCCC)CBr)C.[CH2:28]([CH:30]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:29].Cl[CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59]>CCCCCC.O1CCCC1.O>[CH2:28]([CH:30]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][C:32]1([CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:29]
Reactant: COCCOCCOCCCl
Reactant: CCCCC(CC)CC1c2ccccc2-c2ccccc21
Agent: CCCCC(CC)CBr
Agent: [Li]CCCC
Agent: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCC(CC)CC1(CCOCCOCCOC)c2ccccc2-c2ccccc21
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
7.69 g of butyllithium dissolved in 48 ml of hexane was slowly added during 5 minutes into 20.0 g of fluorene dissolved in 150 ml of anhydrous tetrahydrofuran at -50° C. under nitrogen protection. The mixture was stirred at -30 to 15° C. for 1 hour before it was cooled again to -40 to -50° C. Then, 23.17 g of 2-ethylhexyl bromide was added in 5 minutes. The mixture was subsequently stirred for 2 hours while the temperature was gradually increased to 22° C. The main product in the solution was 9-(2-ethylhexyl)-fluorene as detected by GC-MS. This solution was then cooled to -50° C., and 7.7 g of butyllithium dissolved in 48 ml of hexane was slowly added in 5 minutes under nitrogen protection. The mixture was stirred at -30~15° C. for 1 hour before it was cooled again to -40 to -50° C. Then, 23.75 g of 1-(2-chloroethoxy)-2-(2-methoxyethoxy)-ethane was added in 5 minutes. The mixture was subsequently stirred for 15 hours at 22° C., dispersed in water, and extracted with ether. The etheral solution was washed with water and brine, dried with magnesium sulfate, and evaporated. The residue was distilled to collect 45.5 g (89%) of colorless liquid at 190° C./0.12 mm Hg. MS (m/z): 424 (M+), 277, 205, 191, 178, 165, 133, 103, 59.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][N:4](C(OCC)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[N:1]12[CH2:11][CH2:10][CH2:9][CH:8]1[CH2:7][CH2:6][CH:5]1[CH:2]2[CH2:3][NH:4]1
Reactant: CCOC(=O)N1CC2CC3CCCN3C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C1CC2CCC3NCC3N2C1

Procedure:
9 g (40 mmol) of ethyl 1,4-diazatricyclo -[6.3.0.02,6 ]undecane-4-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is rendered alkaline with potassium carbonate and extracted ten times using 50 ml of chloroform each time, the extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:10])(=[O:9])[N:8]=[CH:7][CH:6]=[CH:5][NH:4]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]I)[CH2:27][CH2:26]1>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:8]2[CH:7]=[CH:6][CH:5]=[N:4][S:3]2(=[O:10])=[O:9])[CH2:27][CH2:26]1
Reactant: O=S1(=O)N=CC=CN1
Reactant: COc1cc2ncnc(N3CCC(CI)CC3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(CN4C=CC=NS4(=O)=O)CC3)c2cc1OC

Procedure:
Sodium hydride (0.20 g. of a 50% dispersion in oil) was added to a stirred solution of 2H-1,2,6-thiadiazine-1,1-dioxide (0.56 g) in dimethylformamide (4 cm3). After 0.5 hours 1-(6,7-dimethoxyquinazolin-4-yl)-4-iodomethylpiperidine (0.70 g) was added and the mixture was warmed at 70° for 10 hours. The solvent was removed in vacuo, water was added and the mixture was extracted with chloroform (4×20 cm3). The dried (MgSO4) extracts were evaporated and the residue was chromatographed on silica (MK 60.9385) eluting with methanol:ethyl acetate, 1:19, to give a foam. Crystallisation from ethyl acetate afforded 1-(6,7-dimethoxyquinazolin-4-yl)-4-(1,1-dioxo-1,2,6-thiadiazin-2-yl)methyl piperidine as white microcrystals, m.p. 173°-174°, (0.27 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:6][C:5]([C:3]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:2])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(-c2ccccc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-1-phenyl-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (29 mg, 0.075 mmol), glycine (750 mg, 10 mmol) and NaOMe solution (15 mL, 7.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (5-70% EtOAc/hexanes+2% AcOH) to give 24 mg of the title compound as a pale yellow solid. MS: (+) m/z 429.99 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: Cc1ccccc1-c1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C23H20ClN5O3, 449.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20](O)=[C:15]2[CH:14]=[N:13]1.O=P(Cl)(Cl)[Cl:24].CN(C)C1C=CC=CC=1>>[Cl:24][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=3[F:1])[N:13]=[CH:14][C:15]=12
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Yield: 95.2 %

Procedure:
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.774 g, 2.51 mmol) was suspended in POCl3 (23 mL, 251 mmol) and dimethylaniline (0.69 mL) and the mixture brought to reflux for 18 h. The solvent was concentrated under reduced pressure and the residue loaded to a column of silica gel. The product was eluted using 5% ethyl acetate/dichloromethane. Removal of solvent afforded 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (0.781 g, 95%). 1H NMR (400 MHz DMSO-d6) δ (ppm): 9.14 (s, 1H); 9.07 (s, 1H); 8.34 (d, 1H); 8.24 (m, 1H); 8.20 (m, 1H); 3.55 (s, 3H). Exact mass calculated for C12H8ClFN4O2S 326, found 327.2 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(C)c(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(Cl)n1
Temperature: 25 °C

Procedure:
4-Chloro-2,6-dimethyl-5-iodopyrimidine and 4-ethynyl-α,α,α-trifluorotoluene were reacted in toluene in the presence of dichlorobis(triphenylphosphine)palladium, cuprous iodide and triethylamine while stirring under room temperature to heating to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].S(OC)([O:16][CH3:17])(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>CO.O>[CH3:1][C:2]1[C:3]([CH2:17][OH:16])=[N:4][CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: Cc1c[n+]([O-])cc(C)c1[N+](=O)[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1cnc(CO)c(C)c1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
3,5-Dimethyl-4-nitropyridine-N-Oxide-dimethyl sulfate adduct (VI) (220 gm, 0.75 mole) was dissolved in methanol (1.0 ltr) and the solution heated to reflux. A solution of ammonium persulfate (140 gm) in water (200 ml) was added dropwise over 4 hours after which reflux was continued for 4 hours. Methanol was distilled off under reduced pressure and the residue was basified to pH 10 by addition of caustic lye (105 ml). The mixture was extracted with dichloromethane (2×400 ml). The dichloromethane layer was dried over sodium sulfate and filtered. The product was used as its solution in dichloromethane for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][CH3:16])=[O:14])[CH2:9][C:8]2=[O:17])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:30]([O:37]CC)(=O)[C:31]([O:33]CC)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:14])[N:15]([CH3:16])[C:31](=[O:33])[C:30]([OH:37])=[C:9]3[C:8]2=[O:17])=[CH:18][CH:19]=1
Reactant: CNC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(O)c2n(c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(4-Fluorobenzyl)-N-methyl-3-oxopiperazine-1-carboxamide (200 mg, 0.75 mmol) was dissolved in anhydrous DMF (1.5 mL) under nitrogen and chilled to 0° C. in an ice-water bath. Lithium bis(trimethylsilyl)amide (0.91 mL, 0.91 mmol, 1M solution in THF) was added dropwise and then diethyl oxalate (0.15 mL, 1.13 mmol) was immediately added. The reaction was allowed to warm to room temperature and stirred for one hour. The solvent was removed in vacuo and the residue partitioned between aqueous HCl and ethyl acetate. The layers were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic extracts were concentrated in vacuo. The residue was triturated with ethyl acetate and the solids were collected by vacuum filtration to yield the title compound as an off-white solid. 1H NMR (400 MHz, d6 DMSO) δ 11.82 (bs, 1H), 7.40 (m, 2H), 7.21 (m, 2H), 4.69 (s, 2H), 3.94 (m, 2H), 3.58 (m, 2H), and 3.21 (s, 3H). HRMS (FT-ICR) C15H14FN3O4+H=320.1047; calculated 320.1041.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH2:27]([N:29]([CH2:39][CH3:40])[CH2:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH2:39]([N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:37][CH:38]=1)[CH3:40]
Reactant: CCN(CC)CCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-diethylamino-ethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8]CC)=[O:7])C.[CH2:13]([O:15][CH:16]([O:20][CH2:21][CH3:22])[CH2:17][NH:18][NH2:19])[CH3:14]>C(O)C.O>[CH2:13]([O:15][CH:16]([O:20][CH2:21][CH3:22])[CH2:17][N:18]1[C:11]([NH2:12])=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=[N:19]1)[CH3:14]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCOC(CNN)OCC
Solvent: O
Solvent: CCO
Product: CCOC(Cn1ncc(C(=O)O)c1N)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 27.6 %

Procedure:
To a suspension of ethyl ethoxymethylenecyanoacetate (21.7 g) in ethanol (65 ml) was added dropwise a solution of hydrazinoacetaldehyde diethyl acetal (19 g) in water (19 ml) under ice-cooling. The mixture was stirred at 80° C. for 1.5 hours and evaporated to remove ethanol. To the residue was 4N sodium hydroxide (64 ml), and the mixture was refluxed for 1 hour. The mixture was adjusted to pH 3.5 with concentrated hydrochloric acid at 10°-20° C., and the resulting precipitate was collected by filtration to give 1-(2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (8.60 g). IR (Nujol) : 3460, 3360, 1645, 1620, 1545 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].CN(C)C=O.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Yield: 109 %

Procedure:
A solution of 2,6-dichloro-4methylbenzoic acid (7.15 g, 34.9 mmol) in thionyl chloride (133 ml) containing dimethylformamide (1.3 ml) was refluxed 3 hours, evaporated under vacuum, and azeotroped twice with benzene. The residue was triturated with petroleum ether (b.p. 30°-60° C., 200 ml) and filtered. The filtrate was evaporated under vacuum to provide 8.5 g (109% of theory) 2,6-dichloro-4-methylbenzoyl chloride, IR (neat): 1785 cm-1. The crude chloride and chlorobenzene (94 g) were stirred in carbon tetrachloride (235 ml), treated in portions with aluminum chloride (5.35 g, 40.1 mmol), kept 30 minutes at ambient temperature, and refluxed 3 hours. The mixture was cooled, quenched by addition of ice and concentrated hydrochloric acid, and extracted three times with dichloromethane. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (400 g) eluted with 3:2 (v/v) dichloromethane-hexane to provide 7.19 g (69%) of 4-(4-chlorobenzoyl)-3,5-dichlorotoluene, m.p. 111.5°-114° C.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])[C:6]([CH:19]([CH3:21])[CH3:20])=[C:5](Cl)[N:4]=1.[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])[C:6]([CH:19]([CH3:21])[CH3:20])=[C:5]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Cc1cc(C#N)cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Sodium (0.48 g, 21 mmol) was reacted with anhydrous benzyl alcohol (20 ml) under nitrogen at room temperature. The mixture was then cooled in an ice bath and (71) (3.22 g, 10 mmol) was added. After 1 hr., the mixture was stirred at room temperature for overnight. The mixture was evaporated in vacuo and the residue was dissolved in ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 3.18 g (68%) of a colorless syrup. 1H NMR (200 MHz, CDCl3) δ 1.28 (6H, d, J=7.2 Hz), 2.39 (3H, s), 3.40 (1H, m), 5.14 (2H, s), 5.42 (2H, s), 7.13-7.44 (13H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:28]
Reactant: CCc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-ethylphenyl borate (0.40 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) to give pale yellow crystals of methyl 7-(4-ethylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (732 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[NH:7][CH:6]=[CH:5]2>C(O)C.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1Br
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
A mixture of 5-bromo-6-nitro-1H-indole (7.5 g, 31.1 mmol) and Raney Ni (1 g) in ethanol was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bromo-1H-indol-6-ylamine (B-27) (2 g, 30%). 1H NMR (DMSO-d6) δ 10.6 (s, 1 H), 7.49 (s, 1 H), 6.79-7.02 (m, 1 H), 6.79 (s, 1 H), 6.14-6.16 (m, 1 H), 4.81 (s, 2 H).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH3:33][CH:34]([CH3:38])[CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:36][CH2:35][CH:34]([CH3:38])[CH3:33])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NCCC(C)C)C3)sc12

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 3-methylbutanal (10.8 μL, 0.010 mmol) and sodium (triacetoxy)borohydride (87 mg, 0.41 mmol), to obtain 34.2 mg of the title compound as a colorless oily substance (99%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:15]=[O:16])[N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1.[CH3:17][N:18]1[CH2:21][CH:20]([CH2:22]O)[CH2:19]1>>[I:1][C:2]1[N:3]=[C:4]2[N:5]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]2[O:16][CH2:22][CH:20]2[CH2:21][N:18]([CH3:17])[CH2:19]2)[CH:6]=1
Reactant: O=Cc1nc(I)cn1CCc1ccccc1
Reactant: CN1CC(CO)C1
Product: CN1CC(COC2c3ccccc3CCn3cc(I)nc32)C1

Procedure:
Compound 7A is obtained following the procedure already described in example 2A starting from compound 4-iodo-1-phenethyl-imidazole-2-carbaldehyde (example 2B) and (1-methylazetidin-3-yl)-methanol to give 2-iodo-4-(1-methylazetidin-3-ylmethoxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 100° C.
Reaction SMILES: [NH2:1][CH2:2][C@:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].C1([C@](O)(CCC)CN[C@H](C2C=CC=CC=2)C)C=CC=CC=1>>[NH2:1][CH2:2][C@@:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCC[C@@](O)(CN)c1ccccc1
Agent: CCC[C@](O)(CN[C@@H](C)c1ccccc1)c1ccccc1
Product: CCC[C@](O)(CN)c1ccccc1
Yield: 89 %

Procedure:
Following the same procedure used for the preparation of (S)-1-amino-2-phenylpentan-2-ol, (2R)-2-phenyl-1-{[(1S)-1-phenylethyl]amino}pentan-2-ol (1.364 g, 4.81 mmol) afforded the desired product (0.768 g, 89%) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.41 (2H, m), 7.33 (2H, t, J=7.71 Hz), 7.18-7.24 (1H, m), 3.11 (1H, d, J=12.38 Hz), 2.84 (1H, d, J=12.38 Hz), 2.39 (3H, s), 1.64-1.74 (2H, m), 1.28-1.40 (1H, m), 0.97-1.08 (1H, m), 0.82 (3H, t, J=7.33 Hz); [α]D20° C.=−8.9° (c=1, EtOH).