Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=[O:14].F[B-](F)(F)F.C([O+](CC)CC)C.[N+](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N-]>ClCCl>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[CH:8]3[CH2:7][CH:6]([CH2:13]3)[C:5](=[O:14])[CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1c2cc(Br)c(F)cc2C2CC1C2
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)C2CC(C2)c2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 6-bromo-7-fluoro-2,3-dihydro-1,3-methanonaphthalen-4(1H)-one (9.00 g, 35.3 mmol) in dry dichloromethane (180 mL) at 0° C. was introduced triethyloxonium tetrafluoroborate (141 mL of a 1.0M solution in dichloromethane, 141 mmol) dropwise over 15 minutes. A solution of ethyl diazoacetate (8.05 g in 75 mL dry dichloromethane, 70.6 mmol) was then added slowly over 20 minutes ensuring the reaction temperature did not rise >3° C. After 30 minutes, the reaction mixture was allowed to warm to room temperature for 16 hr. The solution was then re-cooled to 0° C. and re-treated with triethyloxonium tetrafluoroborate (141 mL of a 1.0M solution in dichloromethane, 141 mmol) and ethyl diazoacetate (8.05 g in 75 mL dry dichloromethane, 70.6 mmol) as described for the first treatment. After warming to room temperature for 5½ hours, the reaction mixture was washed with saturated aqueous sodium bicarbonate (3×100 mL washes), the organic phase dried over sodium sulfate and filtered under vacuum through a Celite 0 pad. The filtrate was adsorbed onto silica gel in vacuo and purified by silica gel flash column chromatography (heptanes/ethyl acetate gradient elution of increasing polarity) to furnish the title compound (8.70 g, 25.50 mmol, 72%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.27 (t, J=7.09 Hz, 4H) 1.84 (dd, J=11.66, 6.62 Hz, 1H) 2.32 (dd, J=12.93, 6.94 Hz, 1H) 2.80 (dt, J=12.61, 7.88 Hz, 1H) 3.04 (dt, J=11.90, 8.55 Hz, 1H) 3.38 (ddd, J=8.83, 7.57, 3.78 Hz, 1H) 3.45 (td, J=8.20, 3.78 Hz, 1H) 4.18-4.29 (m, 2H) 4.78 (s, 1H) 6.88 (d, J=9.14 Hz, 1H) 7.48 (d, J=6.94 Hz, 1H); M+23=363/365.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C(C)=NN4C)=CC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[CH2:38]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([C:54]3[S:55][C:56]4[C:62]([C:63]5[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=5)=[C:61]([C@H:70]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[C:71]([O:73]CC)=[O:72])[C:60]([CH3:81])=[CH:59][C:57]=4[N:58]=3)=[CH:51][CH:52]=2)[C:47]([CH3:82])=[N:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([C:54]3[S:55][C:56]4[C:62]([C:63]5[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=5)=[C:61]([C@H:70]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])[C:71]([OH:73])=[O:72])[C:60]([CH3:81])=[CH:59][C:57]=4[N:58]=3)=[CH:51][CH:52]=2)[C:47]([CH3:82])=[N:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(C)nn4Cc3ccccc3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccc4c(c3)c(C)nn4Cc3ccccc3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid, but using (S)-ethyl 2-(2-(1-benzyl-3-methyl-1H-indazol-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C35H33ClN3O3S: 610.2 (M+H+); found: 610.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 8.12 (dd, J=7.6, 1.6 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J=10 Hz, 1H), 7.69-7.62 (m, 4H), 7.40-7.27 (m, 4H), 5.66 (s, 2H), 5.34 (s, 1H), 2.69 (s, 3H), 2.68 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]1([C:19]#[C:20][CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:20]([CH:21]=[O:22])[C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: O=CC#Cc1ccccc1
Solvent: c1ccccc1
Product: O=Cc1nn2c(=O)[nH]c3ccccc3c2c1-c1ccccc1

Procedure:
4.8 g (0.030 mole) of 3-diazooxindole is suspended in 350 ml of benzene and 3.9 g (0.030 mole) of phenylpropargylaldehyde added. The reaction mixture is refluxed under nitrogen for 48 hours.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)C(N=C=O)(C)C)([CH3:3])=[CH2:2].C(OC1(C)CCCCC1(C)C)(=O)C(C)=C>>[CH3:3][C:1]([C:4]1[CH:5]=[CH:6][CH:13]=[CH:14][CH:15]=1)=[CH2:2]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: C=C(C)C(=O)OC1(C)CCCCC1(C)C
Product: C=C(C)c1ccccc1
Reaction time: 2 h

Procedure:
56.52 g (32.0 m moles) of the aminopropyl-capped PDMS of Example 1 are placed in a 100 mL 3-neck round bottom flask fitted with a mechanical stirrer, gas inlet tube and thermometer. The diamine is cooled with an ice-water bath and kept under a dry air atmosphere. 12.90 g (64.1 m moles) of m-isopropenyl-α,α-dimethylbenzyl isocyanate (TMI) are added while stirring. After 2 hours the mixture becomes very thick and 69.42 g of trimethylcyclohexyl methacrylate (TMMA) are added. The ice-water bath is removed and the contents are stirred for an additional 4 hours to yield a 66.1% solution of α-methylstyrene capped poly(dimethylsiloxane) in TMMA.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(O)c1ccccc1Br
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCc1ccccc1Br

Procedure:
Following General Procedure J and using 1-(2-Bromo-phenyl)-heptan-1-ol (1.86 g, 6.9 mmol), anhydrous dichloromethane (5 mL), trifluoroacetic acid (2.5 mL, 32.5 mmol) and triethyl silane (5 mL, 31 mmol) followed by flash column chromatography, the title compound was obtained (0.4 g, 23%).
Reaction SMILES: [Cl:1][CH:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([N:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH:2]([Cl:1])[CH3:15])=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Cl)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
120.5 g (401 mmol) 6-(2-chloro-propionyl)-3H-benzoxazol-2-one, 49.4 ml (416 mmol) benzylbromide and 57.5 g (416 mmol) potassium carbonate added to 700 ml acetone are stirred overnight at RT. Then the solv. is completely removed i. V. and the residue is extracted with water and DCM. The org. phase is separated off, dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V. The residue obtained is purified through silica gel (eluant: DCM).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:14]1[CH:13]=[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1OC(F)F

Procedure:
A mixture of 20.0 g (65 mmol) of 4-chloro-5-difluoromethoxy-3-(4-chloro-3-methylphenyl)-1-methyl-1H-pyrazole (prepared as described in Example 2), 17.4 g (98 mmol) of N-bromosuccinimide and 200 ml of carbon tetrachloride was refluxed for 3 h under irradiation with a UV lamp. The solid constituents were then filtered off and were washed with a little methylene chloride. The solvent was removed under reduced pressure, and then the residue was purified by chromatography on silica gel (eluent: methylene chloride/hexane=8:2). Yield: 11.0 g; 1H-NMR (270 MHz, in CDCl3); δ [ppm]=7.98 (s, 1H), 7.80 (d, 1H), 7.46 (d, 1H), 6.70 (t, 1H), 4.64 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.CC([O-])(C)C.[K+].O.Cl>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:8])[CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][C:13](=[O:20])[NH:12][C:4]=2[CH:3]=1
Reactant: COC(=O)CCC(=O)Nc1cc(I)ccc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CC(=O)Nc2cc(I)ccc2C1=O
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
To a solution of methyl 4-iodo-2-[(4-methoxy-4-oxobutanoyl)amino]benzoate (24.6 g, 63 mmol) in THF (240 mL) at 10° C. was added a 1 M solution of KOt-Bu in THF (185 mL, 185 mmol) dropwise over 30 min while maintaining the temperature at 10° C. After 2.5 h, 50 mL of H2O followed by 190 mL of 1N HCl were added to bring the solution to pH=4. The resulting mixture was allowed to stir at rt for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (2×200 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give methyl 8-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate (22 g, 97%).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([OH:24])[C:21]#[C:22][CH3:23].[OH-].[Na+].Cl>O>[CH2:20]([O:24][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[C:21]#[C:22][CH3:23]
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC#CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC#CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Temperature: 80 °C
Yield: 300.6 %

Procedure:
To a solution of [4-(4-fluoro-benzoyl)-piperidin-1-yl]-acetic acid (561 mg, 2.11 mmol) in water (10 mL) and was added 2-butyn-1-ol (3.71 g, 52.9 mmol) followed by a solution of 4N NaOH (3.44 mL, 13.8 mmol). The reaction was heated up to 80° C. for 72 hours. The reaction was acidified using 2N HCl to pH 5, then the solvent was then removed under vacuum to afford the crude title compound (2.0 g). LRMS m/z: ES+=315.9 (M+H), retention time 1.52.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=1)([CH3:8])[CH3:7])(=[O:4])=[O:3].[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])([CH3:7])[CH3:8])=[CH:18][CH:17]=4)=[O:15])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(C(C)(C)NS(C)(=O)=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(C(C)(C)NS(C)(=O)=O)cc2)CC1
Yield: 76.4 %

Procedure:
Using methyl 4-(1-methanesulfonylamino-1-methylethyl)benzoate (126 mg) described in Preparation Example 71 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (101 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (162 mg) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(=O)=O>CN(C=O)C>[N:1]1([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cccn2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of pyrazole (100 mg, 1.50 mmol) in DMF (10.0 ml) under nitrogen atmosphere was added sodium hydride (60 mg, 1.65 mmol) and the solution stirred for 5 min. After bubbling ceased, the title compound from Step A (204 mg, 1.50 mmol) in 2.5 mL of DMF was added to the solution. The mixture was placed in a microwave reaction vessel and nitrogen was blown into it before closing.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:31])[C:3]1=[O:20]
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 216°-219° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:29]([O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc([N+](=O)[O-])c1
Yield: 79.3 %

Procedure:
A mixture of 4.0 g (0.029 mol) of 3-nitrophenol, 10.5 g (0.032 mol) of 1-bromooctadecane and 6.0 g (0.043 mol) of anhydrous potassium carbonate in 75 ml of anhydrous DMF was stirred and heated at 75° for 23 hours. The solvent was removed at reduced pressure and water was added to the residue. The product was extracted with ether and the dried extract was concentrated at reduced pressure to a solid which was purified by HPLCusing 15% methylene chloride-hexane to give 9.0 g (80% yield) of 3-(octadecyloxy)nitrobenzene.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:33]=[C:32]([N+:34]([O-])=O)[CH:31]=[CH:30][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:34][C:32]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:33]=1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 9 h
Yield: 104 %

Procedure:
After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(2-dimethylaminoethyl)piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (94 mg) under a nitrogen atmosphere, 10% palladium-carbon (46 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 9 hours. The atmosphere in the reaction vessel was then replaced with nitrogen, and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of 4-(2-dimethylaminoethyl)piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (91 mg) as a pale yellow amorphous substance.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(OCC)(=O)C>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(N3CCOCC3)ncc2Cl)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
A 1,4-dioxane (1.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (100 mg, 0.24 mmol) obtained in Example 54 and morpholine (200 μl) was stirred at 100° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and brine, dried and then concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (100 mg, 89%) as an oil.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[CH2:11][NH:12][C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:17]=1[C:30]([NH2:32])=[O:31])=[O:14]>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][CH2:11][NH:12][C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[C:17]=1[C:30]([NH2:32])=[O:31])=[O:14])(=[O:7])[CH3:6]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Acetic anhydride (4.2 g 0.041 mol) was added to a solution of 5-({[(3-hydroxypropyl)amino]carbonyl}amino)-3-(4-nitrophenyl)isothiazole-4-carboxamide (12.0 g, 0.032 mol) in pyridine (120 mL) at ambient temperature over 10 min. The resulting mixture was stirred at ambient temperature for 2 hr. The reaction mixture was concentrated in vacuo. The residue taken in EtOAc (500 mL) and washed with water and brine then dried (sodium sulfate), filtered, solvent concentrated in vacuo to give the title compound as a yellow solid (12.2 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[S:8][CH2:9][CH2:10]1
Reactant: CC(C)=CCSc1cccc(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)SCCC2(C)C

Procedure:
7 g (36.4 mmol) of 1-methyl-3-(3-methylbut-2-enyl)sulphanylbenzene and 50 ml of toluene are introduced into a round-bottomed flask and 10.4 g (54.6 mmol) of para-toluenesulphonic acid are added. The mixture in refluxed for four hours. The reaction medium is evaporated to dryness, the residue is taken up in water and ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 6.8 g (97%) of the thiochroman are collected in the form of a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:32]([C:31]3[CH:30]=[CH:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[CH:35][CH:34]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Product: CN1CCN(c2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Br)cnc4[nH]3)cc2)CC1
Yield: 48.7 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 4-(4-methyl-piperazin-1-yl)-benzaldehyde (26.6 mg, 0.130 mmol) were reacted to produce 30 mg (49%) of the title compound. mp: 215-218° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.99 (s, 1H), 7.97 (s, 2H), 7.73 (s, 1H), 7.20 (s, 1H), 7.07 (d, J=8 Hz, 2H), 6.99 (d, J=8 Hz, 1H), 6.37 (br s, 2H), 5.27 (t, J=8 Hz, 1H), 3.32 (s, 6H), 2.88 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=7 Hz, 1H), 2.45 (br s, 4H), 2.23 (s, 4H). MS: 522, 524 (M+H), HPLC: 1.86 min (G method).
Reaction SMILES: [N:1]1([C@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([C:20]5[CH:21]=[N:22][NH:23][CH:24]=5)[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][N:23]1[CH:24]=[C:20]([C:18]2[CH:17]=[CH:16][C:14]3[N:15]=[C:11]([C@H:9]4[CH2:8][C@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:10]4)[S:12][C:13]=3[CH:19]=2)[CH:21]=[N:22]1
Reactant: c1cc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2cc1-c1cn[nH]c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product of Example 51B (34.0 mg, 0.10 mmole) was dissolved in DMF (2 ml) and then cooled to 0° C. NaH (60%, 44.0 mg, 1.1 mmol) was added under N2, and the reaction was stirred at 0° C. for 0.5 hours. Iodomethane (6.8 μl, 0.11 mmole) was added, and the reaction mixture was stirred at 0° C. for 1 hour, and then slowly raised to room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (4×5 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (10% methanol in dichloromethane) to give 23.8 mg (67.6%) of title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.94 (d, J=8.48 1H) 7.93 (d, J=2.03 1H) 7.80 (s, 1H) 7.66, (s, 1H) 7.56 (dd, J=8.48, 2.03 1H) 3.80 (s, 3H) 3.87 (m, 1H) 3.27 (m, 1H) 2.38-2.62 (m, 4H) 1.49-1.76 (m, 6H). MS: (M+H)+=353.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: c1ccccc1
Agent: Cl
Agent: O=C(O)CCCBr
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Product: O=C(CCCBr)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In this Example, 14.2 g of 4-bromobutyric acid (85 mmol) was dissolved in 10 g of benzene (128mmol) and, after the temperature was raised to 60° C., 11.9 g of thionyl chloride (100 mmol) was dropwise added. Thereafter, the temperature was raised to 65 to 75° C. and the mixture was stirred at that temperature for one hour. Then, after the mixture was cooled to 20° C., the reaction solution was dropwise added into a suspension solution of 30 g of benzene (256 mmol) and 12 g of aluminum chloride (90 mmol) at 10° C. After stirring the mixture at that temperature for one hour, the temperature was raised to 20° C. and the mixture was further stirred for 30 minutes and added into a 10% aqueous solution of hydrochloric acid that had been cooled to 10° C. Then, the aqueous phase was extracted with benzene, and the organic phase was washed with diluted hydrochloric acid, an aqueous solution of sodium hydrogencarbonate, an aqueous solution of sodium hydroxide, and brine, followed by removing the solvent by distillation under reduced pressure to give 4-bromobutyrophenone in a 62.0% yield from 4-bromobutyric acid.