Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([OH:16])=O)=[N:3]1.C[N:18]1[C:26](C(O)=O)=[C:25]2[C:20]([CH:21]=C([N+]([O-])=O)C=C2)=N1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([N:18]2[CH2:21][CH2:20][CH2:25][CH2:26]2)=[O:16])=[N:3]1
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1C(=O)O
Reactant: Cn1nc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Product: Cn1nc(C(=O)N2CCCC2)c2ccc([N+](=O)[O-])cc21

Procedure:
is obtained by reacting a mixture of 1-methyl-6-nitro-1H-indazole-3-carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid. The product is purified by chromatography on silica gel.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[N:10]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[N:10]=1
Reactant: C1=COCCC1
Reactant: OCCSc1ccc2nccn2n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Product: c1cn2nc(SCCOC3CCCCO3)ccc2n1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
In 30 ml of 1,2-dichloroethane is suspended 1.5 g of 6-(2-hydroxyethylthio)imidazo[l,2-b]pyridazine and with stirring at room temperature, 1.94 g of dihydropyran and 193 mg of pyridinium p-toluenesulfonate are added. The mixture is stirred at 65° C. for 4 hours, after which 1.5 g of dihydropyran and 100 mg of pyridinium p-toluenesulfonate are further added. The mixture is stirred for an additional 4 hours. After cooling, the reaction mixture is washed with 30 ml portions of water three times, dried over sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel (100 g) column chromatography and elution is carried out with ethyl acetate. The eluate is concentrated under reduced pressure to give 1.85 g of 6-[2-(2-tetrahydropyranyloxy)ethylthio]imidazo[l,2-b]pyridazine as colorless crystals melting at 60° to 62° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([O:15][C:36](=[O:38])[CH3:37])[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)N(CCN(C)C(=O)OCc2ccccc2)c2ccc(C)cc2S[C@H]1c1ccc(C)cc1

Procedure:
A mixture of 0.73 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5 ml of acetic anhydride and 0.1 ml of pyridine is treated in the same manner as described in Example 1-(2), whereby 0.92 g of (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as an oil. (3) A mixture of 0.92 g of (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2 ml of 25% hydrogen bromide-acetic acid and 2 ml of acetic acid is stirred at room temperature for 2 hours. The mixture is evaporated under reduced pressure to remove solvent. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. Ether is added to the residue, and the resultant crystals are collected by filtration and washed with ether. A mixture of the crystals thus obtained, 2 ml of ethanol and 2 ml of an aqueous 5% sodium hydroxide solution is stirred at room temperature for 2 hours. The mixture is adjusted to pH 8 with acetic acid, and then extracted with chloroform. The extract is washed with water, dried and evaporated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and recrystallized from isopropanol. 0.32 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hemihydrate is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][CH2:3]1.[Br:13]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:13][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:12])([CH3:1])[CH2:3][NH:4]2)=[CH:9][C:8]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1ccc2c(c1)C(C)(C)CN2
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1cc2c(cc1Br)NCC2(C)C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
3,3,5-Trimethyl-2,3-dihydro-1H-indole (1.84 g, 11.43 mmol) was dissolved in concentrated sulfuric acid (25 mL) and silver sulfate (1.90 g, 6.06 mmol) added. The reaction was stirred for 1 h and bromine (0.6 mL, 11.77 mmol) was added over 5 minutes. The reaction was stirred at this temperature for 1 h and very slowly quenched by slow addition to 50% aqueous sodium hydroxide (100 mL) with ice cooling (CAUTION,). Further aqueous sodium hydroxide was added to adjust pH to basic. The resulting mixture was extracted with diethyl ether (3×) and the organic phase dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-50%, EtOAc in petrol 40-60), to give the title compound (1.30 g), MS: [M+H]+=241.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23][C:24]([CH3:33])([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:25](Cl)=[O:26]>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:25](=[O:26])[C:24]([CH3:33])([CH3:23])[CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(=O)OCC(C)(C)C(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)C(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C
Yield: 63 %

Procedure:
To the mixture of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (3.0 g, 10 mmol), TEA (15 mL), and DMAP (1.25 g, 10 mmol) in THF (15 mL) was added 2,2-dimethyl-3-acetyloxypropionyl chloride (3.58 g, 20 mmol) prepared in Step A. After the reaction mixture was refluxed for 48 h (90-110° C.), the solvent was removed, and the residue was diluted with an aqueous NaHCO3 solution was added to the residue. The organic material was extracted with EtOAc, and the extracts were washed by 1N HCl, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (2.80 g, 62.9%).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][O:15][C:16]=2[N:17]=1)[CH:3]([CH3:5])[CH3:4].[ClH:25].C(OCC)(=O)C>>[ClH:25].[CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][O:15][C:16]=2[N:17]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@H](C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of the compound obtained in step 1 (0.79 g) and 4N hydrogen chloride/ethyl acetate (10 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized twice from ethanol-diisopropyl ether to give the title compound (0.48 g, 75%) as a white powder.
Reaction SMILES: Cl.N[N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]#[N:9].C(O)(=O)C.[CH:14]([NH2:16])=[NH:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>C(O)C>[N:15]1[N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[C:8]([NH2:9])=[N:16][CH:14]=1
Reactant: N=CN
Reactant: N#Cc1cccn1N
Agent: Cl
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncnn2cccc12
Yield: 43.9 %

Procedure:
To a stirred suspension of 1-Amino-1H-pyrrole-2-carbonitrile hydrochloride (50 g, 0.35 mol) in absolute ethanol (800 mL) was added formamidine acetate (181.3 g, 1.74 mol) and potassium phosphate (370 g, 1.74 mol). The suspension was heated for 18 hours@78° C. (under N2), then cooled, filtered and concentrated to dryness in vacuo. The residue was mixed with ice water (2 L) and the dark grayish-brown solids were collected by suction filtration. The filter cake was washed with water, sucked dry and the solids were dissolved (on the funnel) with hot ethyl acetate and filtered into a collection vessel. The dark solution was filtered through a long plug of 30/40 Magnesol and the pale yellow filtrate was concentrated to dryness in vacuo to afford a yellow-tinged solid (20.6 g, 44.1% yield). The plug was washed with ethyl acetate/ethanol and the washings were concentrated in vacuo to afford additional material, 10.7 g (23%). Extraction of the aqueous work-up filtrate with ethyl acetate followed by drying, Magnesol filtration and concentration gave another 6.3 g (14%) of clean product, bringing the total recovery to 37.6 g (81%). 1H-NMR (CD3OD): δ 7.72 (s, 1H), 7.52 (dd, 1H, J=2.5, 1.6 Hz), 6.85 (dd, 1H, J=4.5, 1.6 Hz), 6.64 (dd, 1H, J=4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([OH:22])=[CH:15][CH:14]=3.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([O:22][CH2:38][C:37]1[C:36]([F:35])=[CH:43][CH:42]=[CH:41][C:40]=1[F:44])=[CH:15][CH:14]=3
Reactant: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(O)ccc12
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3c(F)cccc3F)ccc12
Temperature: 130 °C
Reaction time: 3 h

Procedure:
1 g 1-(2-Chloro-phenyl)-3,4-dimethyl-7-hydroxy-imidazo(1,5-a)quinoxaline, 2.24 g Caesium carbonate, 50 mL N,N-dimethylformamide, and 6 mL water were stirred for 10 min followed by addition of 0.83 g 2,6-difluorobenzylbromide. After 3 h stirring at 130° C. the reaction mixture was given into 150 mL water, filtered off, washed with water, dried under reduced pressure, and purified with silica gel, dichloromethane/methanol=95/5.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]>>[OH:15][C:14]1[CH:21]=[CH:20][C:18]([O:19][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(O)c1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid was reacted with hydroquinone to produce 4-(4-Hydroxy-phenoxy)-3-nitro-benzoic acid according to the procedure of Example 54A, which was treated sequentially with Benzyl-methyl-amine using the procedure from Example 54B and reduced using the procedure from Example 54C to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=3)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 70.4 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.332 g, 0.891 mmol) and tert-butyl piperidin-4-yl-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate (0.194 g, 0.891 mmol) gave tert-butyl (S)-{1-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperidin-4-yl}-N-[2-(4-trifluoromethylphenyl)-ethyl]carbamate (0.370 g, yield 70%) as a light yellow oil in the same manner as in Example 277.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]([OH:15])=O)=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][NH2:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][NH:32][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:15]
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)[nH]c2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)[nH]c2c1

Procedure:
To a solution of 2-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (Compound 155, 10 mg, 0.046 mmol) in CH2Cl2 (1 ml) was added i-Pr2NEt (17 μl, 0.098 mmol) and 3,4-difluorobenzylamine (11 μl, 0.092 mmol), followed by BOP. After completion, the reaction was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1(O)[CH2:15][CH2:14][CH2:13][C:12]2[N:11]=[CH:10][N:9]=[CH:8][C:7]1=2.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[C:7]2[CH:8]=[N:9][CH:10]=[N:11][C:12]=2[CH2:13][CH2:14][CH:15]=1
Reactant: COc1ccc(Br)c(OCC2(O)CCCc3ncncc32)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Br)c(OCC2=CCCc3ncncc32)c1

Procedure:
A solution of 10 mmol of 5-(2-bromo-5-methoxyphenoxymethyl)-5,6,7,8-tetrahydroquinazolin-5-ol and 20 mmol of phosphorus oxychloride in 20 ml of pyridine is heated at reflux for 0.5-1 hour. The mixture is poured onto ice and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the bias of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH:17][CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: CCCC(NCCC(=O)OC)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 20 h

Procedure:
A mixture of 1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine (2 g), methyl acrylate (2 g) and toluene (10 ml) was heated under reflux with stirring for a total of 20 hours. Methyl acrylate (0.5 ml) was added, and heating under reflux and stirring were continued for 3 days. The solvent was removed in vacuo, and the oily residue as purified by chromatography on a silica column using a mixture of 9 parts petroleum ether (b.p. 40°-60°) and 1 part acetone as eluant. From the eluate methyl 3-{1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamino}propanoate was obtained as a pale yellow oil, the physical properties of which were not determined.
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:35]=1)[C:22]1[CH:21]=[C:20]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=[O:37]>>[NH2:5][C:6]1[S:7][CH2:8][C@:9]2([N:35]=1)[C:10]1[CH:11]=[C:12]([C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[C:22]2=[CH:21][C:20]([C:23](=[O:37])[CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:19][CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)C#Cc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Product: CC(C)(C)CC(=O)c1ccc2c(c1)[C@]1(CSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A resealable tube charged with N-tert-butyl-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (0.113 g, 0.234 mmol) and TFA (2 mL) was sealed and heated to 160° C. After 3 hrs, the solvent was removed in vacuo and the residue taken up in 2 mL DCM. TEA (ca. 0.1 mL) was added and the solution was loaded onto a silica gel plug and purified by silica gel chromatography using 2-4% MeOH:DCM w/1% NH4OH to afford crude, racemic product that was resolved by chiral column chromatography to give both (R) and (S)-1-(2-amino-2′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthene]-7′-yl)-3,3-dimethylbutan-1-one. MS Found: MH+=445.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[N:29])[C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][O:26][CH3:27])[CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[N:29])[C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][O:26][CH3:27])[CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=[S:40])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Product: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-2H-1,4-benzodiazepin-2-thione (IIv) was prepared by reacting 0.00052 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-2H-1,4-benzodiazepin-2-one (Iv) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][CH2:7][CH2:8][C@@H:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:11]S(C)=O>ClC1C=CC=CC=1Cl>[OH:6][CH2:7][CH2:8][C@@H:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=[CH2:11]
Reactant: CS(=O)CC[C@@H](CCO)NC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: C=C[C@@H](CCO)NC(=O)OC(C)(C)C
Temperature: 166 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
Sodium acetate (13.45 g) was added to a solution of tert-butyl ((3R)-1-hydroxy-5-(methylsulfinyl)pentan-3-yl)carbamate (9.38 g) obtained in Step 2 in 1,2-dichlorobenzene (140 ml) at room temperature. The mixture was stirred at an internal temperature of 166° C. for 18 hours. After cooling the reaction mixture, the insoluble matter was filtered off, and 1,2-dichlorobenzene was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium chloride solution, water, and a saturated sodium chloride solution; and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound 2.50 g as a light-yellow, oily substance.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCCn1cnc(C(=O)OCC)c1Br
Reactant: COCOc1cc(OC)ccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCn1cnc(C(=O)OCC)c1-c1ccc(OC)cc1OCOC
Yield: 44.7 %

Procedure:
A mixture of ethyl 5-bromo-1-n-butyl-1H-imidazole-4-carboxylate (0,10 g, 0.37 mmol), 2-methoxymethoxy-4methoxyphenylboronic acid (0.16 g, 0.73 mmol), sodium carbonate (0.08 g, 0.73 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.04 g) in 12 mL of toluene/ethanol/water (10/1/1) was stirred at reflux for 24 h. After an aqueous work up, extracting with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.06 g, 46%). 1H NMR (250 MHz, CDCl3) δ 7.53 (s, 1H), 7.09 (d, 1H), 6.75 (d, 1H), 6.60 (dd, 1H), 5.05 (q, 2H), 4.21 (q, 2H), 3.85 (s, 3H) 3.80 (t, 2H), 3.30 (s, 3H) 1.60 (quintet, 2H), 1.30 (m, 5H), 0.80 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH2:21])[CH2:14]1.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[F:22][C:23]([F:30])([F:29])[C:24]([NH:21][CH2:20][CH2:19][NH:18][CH:15]1[CH2:16][CH2:17][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:14]1)=[O:25]
Reactant: COc1ccc2nccc(N3CCC(NCCN)C3)c2n1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc2nccc(N3CCC(NCCNC(=O)C(F)(F)F)C3)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of N1-[1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl]-ethane-1,2-diamine (1.3 g, 4.53 mmol) in THF (50 mL) at 0° C. was slowly added ethyl trifluoroacetate (1.19 mL, 4.53 mmol). The solution was stirred for 1.5 h and concentrated. The resulting solid was used without further purification (1.73 g, quantitive): LC/MS m/z 384 (M+H)+.