Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[CH:27]1([S:33][CH2:34][CH2:35]Cl)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CO>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:35][CH2:34][S:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reaction time: 20 h
Yield: 53 %

Procedure:
A stirred mixture of 0.54 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate, 0.295 g of 2-chloroethyl cyclohexyl sulfide, 0.23 g of potassium carbonate, and 0.27 g of potassium iodide in 9 cm3 of acetonitrile and 1 cm3 of methanol was brought to a temperature in the region of the boiling point under an inert atmosphere for 20 hours. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under an argon pressure of 80 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 35 cm), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 23 to 40 were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.4 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a brown color.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22]CCCl.O=P(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:22])=[N:14][CH:13]=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]c(=O)c2ccc(SCc3ccccc3)cc12
Reactant: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A vial was charged with 6-(benzylthio)-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile (0.492 g, 1.683 mmol) and DCE (8.41 ml). POCl3 (0.314 ml, 3.37 mmol) was added and the reaction was stirred overnight at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (40 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford 6-(benzylthio)-1-chloroisoquinoline-4-carbonitrile as a brown solid. m/z (ESI) 311.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[N:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:19][C:21]3[CH:53]=[CH:52][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]4=[O:51])=[CH:23][CH:22]=3)[CH3:14])[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1cncc(-c2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cncc(-c2ccccc2)c1
Yield: 59 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 419 mg of 2-[1-(3-phenyl-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 18), 585 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 429 mg of triphenylphosphine and 285 mg of diethyl azodicarboxylate, 522 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1([C:7]([O-:9])=[O:8])[CH2:6][CH2:5]1.Cl.[C:13]1(C)[CH:18]=CC=C[CH:14]=1>>[CH:13]([CH:5]1[CH2:6][C:4]1([OH:3])[C:7]([OH:9])=[O:8])([CH3:18])[CH3:14]
Reactant: C[Si](C)(C)OC1(C(=O)[O-])CC1
Reactant: Cc1ccccc1
Agent: Cl
Product: CC(C)C1CC1(O)C(=O)O
Reaction time: 1 h

Procedure:
17.0 g (0.06 mole) of trimethylsilyl 2-isopropyl°-1-trimethylsiloxy-cyclopropanecarboxylate were stirred for 2 hours at 30° C. in 100 ml of toluene saturated with hydrogen chloride. Dry nitrogen was then passed through the solution for 1 hour and the precipitate was filtered off. Crystallization from xylene yielded 2-isopropyl-1-hydroxycyclopropanecarboxylic acid (6.1 g) with a melting point of 135° to 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]=[N+:16]=[N-:17])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
To a suspension of 12 g of 2-chloro-5-chlorosulphonylbenzoic acid in 150 ccs of ethanol, a solution of 10 g of sodium azide in 30 ccs of water and 120 ccs of ethanol is dropwise added whilst stirring. Stirring is continued overnight and the inorganic constituents are precipitated with acetone. After allowing to stand at 0° C for a relatively long period, the precipitate is filtered off and the mother liquor is carefully evaporated to dryness by means of a rotary evaporator.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][N:8]([CH2:14][CH3:15])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:24]=[C:25]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH2:7][N:8]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:14][CH3:15])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid(5-bromo-2-iodo-benzyl)-ethyl-amide and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][C:37]1[CH:41]=[C:40]([CH2:42][NH:43][C:44]2[CH:53]=[CH:52][CH:51]=[CH:50][C:45]=2[C:46](OC)=[O:47])[O:39][N:38]=1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[NH:15][N:16]=[C:12]([NH:11][C:46](=[O:47])[C:45]3[CH:50]=[CH:51][CH:52]=[CH:53][C:44]=3[NH:43][CH2:42][C:40]3[O:39][N:38]=[C:37]([CH3:36])[CH:41]=3)[CH:13]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccccc1NCc1cc(C)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccccc3NCc3cc(C)no3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 10505.6 %

Procedure:
NaHMDS (1M solution in THF, 0.83 ml, 0.828 mmol, 2.5 eq) was added dropwise to a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (90 mg, 0.364 mmol, 1.1 eq) and methyl 2-{[(3-methylisoxazol-5-yl)methyl]amino}-benzoate (115 mg, 0.33 μmol, 1 eq), stirred in THF (4 ml) under nitrogen. The solution was stirred at room temperature for 50 mins. The solution was quenched with satd. aq. NH4Cl, diluted with water (5 ml) and extracted with ethyl acetate (3×8 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0-1.5% MeOH in DCM. Fractions containing product were evaporated and further purified by reverse phase prep. HPLC purification, eluting with a gradient of MeCN/H2O+0.1% TFA to afford the title compound as an off-white solid (16 mg, 10% yield); 1H NMR (399.902 MHz, DMSO) δ 2.20 (s, 3H), 2.88 (s, 4H), 3.73 (s, 6H), 4.57 (s, 2H), 6.21 (s, 1H), 6.33 (t, 1H), 6.41 (bs, 1H), 6.43 (d, 3H), 6.65 (t, 1H), 6.77 (d, 1H), 7.28-7.34 (m, 1H), 7.75-7.79 (m, 1H), 8.10 (bs, 1H), 10.50 (s, 1H). MS: m/z 462 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 65 %

Procedure:
A mixture of 180 mg (0.36 mmol) of (2S,3R,4R,5S)-2,5-di(N-((t-butyloxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane and 180 mg of 5% rhodium on carbon in 50 ml of methanol was shaken under 4 atmospheres of hydrogen for 24 h. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 5% ethyl acetate in hexane to provide 120 mg (65%) of the desired compound (Rf 0.35, 30% ethyl acetate in hexane) as a white solid, m.p. 224°-226° C. Mass spectrum: (M+H)+ =513.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([NH:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:20]1=[O:40])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:20]2=[O:40])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC2CC2)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-2,3-dihydro-1-cyclopropylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the title compound was prepared as a solid (mp.=203-205° C.). The product was purified by slurrying in ether/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Sn](Cl)Cl>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(F)cc2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1cc(F)cc2cccnc12
Yield: 74.1 %

Procedure:
In a similar fashion using route 1 general procedure 4, 6-fluoro-8-nitroquinoline (Intermediate 36) (1.0 g, 5.41 mmol), tin (II) chloride (3.08 g, 16.2 mmol) and 6N HCl (5 drops) gave the title compound (650 mg, 74%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)[CH3:33]>COCCOC>[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:33]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 35.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-ethylphenylboronic acid (27 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.024 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product (19 mg, 36%). MS m/e 435.44 (M+H+)
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([CH3:34])=[C:6]([C:8]2[N:9]([CH2:24][C:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[S:27][CH:26]=3)[N:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH2:20][CH:21]([CH3:23])[CH3:22])[N:7]=1.[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([CH2:24][N:9]2[C:8]([C:6]3[N:7]=[C:3]([NH:2][C:35](=[O:37])[CH3:36])[S:4][C:5]=3[CH3:34])=[C:16]3[C:11]([N:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13](=[O:19])[N:14]([CH3:18])[C:15]3=[O:17])=[N:10]2)=[CH:26]1
Reactant: CC(=O)Cl
Reactant: Cc1sc(N)nc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1csc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2csc3ccccc23)c(C)s1

Procedure:
3-(2-amino-5-methyl-1,3-thiazol-4-yl)-2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione hydrochloride was reacted with excess acetyl chloride using triethylamine as a base. The resulting bis acetylated product is treated with potassium carbonate to give the title compound. Mass: 523.22 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].Cl.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.N1C=CC=CC=1.Cl>CN(C=O)C>[CH2:5]([O:4][C:2](=[O:3])[NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([Br:10])=[CH:12][CH:13]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)COC(=O)NCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
Isobutyl chloroformate (0.152 ml, 1.17 mmol) was added to a solution of 4-bromo-benzylamine hydrochloride (200 mg, 0.899 mmol) and pyridine (0.182 ml, 2.25 mmol) in DMF (2.0 ml), and the mixture was stirred at room temperature for 1.5 hours. A 1 N aqueous HCl solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give (4-bromo-benzyl)-carbamic acid isobutyl ester (180 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[CH2:20]O.P(Br)(Br)[Br:23]>C(OCC)C>[Br:23][CH2:20][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:4]=1
Reactant: Cc1c(-c2cc(CO)c(Cl)cc2F)nn(C)c1C(F)(F)F
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cc1c(-c2cc(CBr)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 7.0 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol in 200 mL of diethyl ether was added 30 mL of phosphorus tribromide and the mixture allowed to stir overnight. The reaction mixture was poured into ice water, the ether removed by concd in vacuo and the resultant solid collected by filtration. The solid was washed with water and air dried to give a quantitative yield of 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole: 1HNMR (CDCl3) δ 2.17 (t. 3H, 2.0 Hz), 4.07 (s, 3H), 4.64 (s, 2H), 7.30 (d, 1H, 9.5 Hz), 7.62 (d, 1H, 7.5 Hz); 19FNMR (CDCl3) δ -58.5 (s, 3F), -111.6 (s, 1F).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[C:10]([C:14]1[C:15]([Cl:22])=[CH:16][C:17]([I:21])=[C:18]([OH:20])[CH:19]=1)([CH3:13])([CH3:12])[CH3:11]>CC(=O)CC>[C:10]([C:14]1[C:15]([Cl:22])=[CH:16][C:17]([I:21])=[C:18]([O:20][CH2:8][CH3:9])[CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CCI
Reactant: CC(C)(C)c1cc(O)c(I)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1I
Temperature: 80 °C
Yield: 80.2 %

Procedure:
Potassium carbonate (8.0 g, 58.0 mmol) and iodoethane (3.0 mL, 37.7 mmol) were added to a stirred solution of 5-t-butyl-4-chloro-2-iodophenol (2.4 g, 8.1 mmol; prepared according to Fukata et al. Bull. Chem. Soc. Jpn. 1994, 67, 592-594) in 2-butanone (50 mL). The resulting mixture was heated in an oil bath (80° C.) for 16 h and then allowed to cool. The solution was concentrated and redisolved in methylene chloride. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated to give 4-tert-butyl-5-chloro-2-ethoxy-1-iodobenzene (2.2 g, 85%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>O1CCCC1>[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:44])=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccc(F)cc3)CC4)nc12
Yield: 49 %

Procedure:
To a suspension of 0.037 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3 ml tetrahydrofurane were added at 0–4° C. 0.06 ml N-ethyldiisopropylamine and 0.01 μl 4-fluorobenzoylchloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.022 g (49%) (4-fluoro-phenyl)-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; M.p.: 205–207° C.; MS (ISP): m/e=506 (M−H+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[CH:37]=[CH:36][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:29])=[CH:36][CH:37]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 80 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide (Intermediate 29, 100 mg) in chloroform (4 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (0.5 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](Br)[CH3:10])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH2:25]>C(OCC)(=O)C>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH:25][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:10]
Reactant: CC(Br)c1cnc(Cl)nc1Cl
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)c(NC(C)c2cnc(Cl)nc2Cl)c1
Temperature: 90 °C

Procedure:
(±)-2,4-Dichloro-5-(1-bromoethyl)-pyrimidine (0.20 g; 0.79 mmol) (from Example 1c supra), N,N-diisopropylethylamine (0.40 mL; 2.27 mmol) (Aldrich) and 2-chloro-5-methoxyaniline hydrochloride (0.15 g; 0.77 mmol) (Aldrich) were combined (neat) and heated in an oil bath at 90° C. for 16 hours. Upon cooling, the mixture was taken up in ethyl acetate and washed with water and then brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (Biotage 40M; 5:95 to 15:85 ethyl acetate-hexanes gradient) gave (±)-(2-chloro-5-methoxy-phenyl)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-amine. (Yield 0.12 g; 45.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=O.[Br-].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:51]=[CH:52][CH:53]=1)[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=[CH:31][C:30]1[CH:51]=[CH:52][CH:53]=[C:28]([O:27][CH3:26])[CH:29]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Reactant: COc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Product: COc1cccc(C=Cc2cc(Oc3c(C)cc([N+](=O)[O-])c4c3CCC4)ccc2OC)c1

Procedure:
4-{4-Methoxy-3-[2-(3-methoxyphenyl)vinyl]phenoxy}-5-methyl-7-nitroindane was prepared in a similar manner to those described in Reference Example 15 using 2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde instead of 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde and using (3-methoxybenzyl) triphenylphosphonium bromide instead of furfuryltriphenylphosphonium bromide.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[NH:4][C:3]1=[S:14].[C:15]([O-])([O-])=O.[Na+].[Na+].CI>CC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[S:14][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=S)[nH]c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cc([N+](=O)[O-])ccc2n1C

Procedure:
A mixture of 1-Methyl-5-nitro-1,3-dihydro-benzoimidazole-2-thione (5.16 g, 24.7 mmol), Na2CO3 (2.88 g, 27.2 mmol) and MeI (3.68 g, 25.94 mmol) in acetone (150 ml) was refluxed overnight. The mix was filtered hot and the filtrate was concentrated to about 50 ml, the product was collected by filtration and washed with a small amount of cold CH2Cl2, drying left 4.58 g as a mustard yellow solid: LC/MS(m/e) at 224.0 [M+H]+, Rt at 1.55 min.