Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]2[C:19]3[C:26]([CH3:27])=[C:25]([C:28](O)=[O:29])[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:6]1)(=[O:3])[CH3:2].Cl.[NH2:32][C@@H:33]1[CH2:35][C@H:34]1[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:38][C:37](=[O:43])[NH:36][CH:34]1[CH2:35][CH:33]1[NH:32][C:28]([C:25]1[S:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:17][C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][C@H:7]3[CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:8]3)[C:19]=2[C:26]=1[CH3:27])=[O:29])([CH3:40])([CH3:42])[CH3:41]
Reactant: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1N
Agent: Cl
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NC4CC4NC(=O)OC(C)(C)C)c(C)c23)C1

Procedure:
Prepared analogously to 35.3 from 0.080 g 4-[2-(trans-3-acetylamino-cyclobutoxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 35.2) and 0.050 g tert-butyl (1R,2R)-2-aminocyclopropylcarbamate hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH3:16][N+:17]([O-:19])=[O:18]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:10][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: COCCOCOc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: COCCOCOc1ccc(/C=C/[N+](=O)[O-])cc1
Yield: 79 %

Procedure:
A mixture of 4-((2-methoxyethoxy)methoxy)benzaldehyde (Intermediate I, 1.86 g, 8.85 mmol) and NH4OAc (0.75 g, 9.73 mmol) in dry THF (15 mL) and CH3NO2 (15 mL) was refluxed for 20 h and allowed to reach room temperature. The volume of the reaction was reduced to aprox. ⅓, by rotatory evaporation; the resulting solution was poured into water (15 mL) and extracted with AcOEt (2×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual brown oil was purified by column chromatography on silica gel (15-30% EtOAc/Hexanes) affording 1.77 g of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene [Rf=0.7 (50% AcOEt/Hexanes), yellow solid, 79% yield].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:36])[CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:38].[Na+].[Na+]>C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:36])[CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:19][CH:20]=4)[C:15](=[O:38])[C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCCN1CCCCC1)c1ccc2oc3ccc(C(=O)CCCN4CCCCC4)cc3c(=O)c2c1
Reaction time: 2 h

Procedure:
To a solution of 9.8 g (0.025 mole) of 2,7-bis(4-piperidinobutyryl)xanthene in 300 ml of glacial acetic acid is added 9.8 g (0.033 mole) of sodium dichromate over one-half hour. The mixture is stirred for 11/2 hours, refluxed for 1 hour, then evaporated to near dryness, cooled, diluted with water and made alkaline with 28% NH4OH solution. The resulting solid is extracted with methylene chloride, chromatographed on alumina using methylene chloride as the eluant, recrystallized from heptane and dried under vacuum at 60° C. to give the title compound, M.P. 93°-95° C.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:26])[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C:11]=2[CH:12]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:26]=[C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(C#N)c(=O)n2-c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(n(-c3ccccc3)c1=O)CCNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-cyano-2-oxo-1-phenyl-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate (150 mg, 0.427 mmol) was dissolved in CH2Cl2 (3 mL) and TFA (0.3 mL). The mixture was stirred at room temperature overnight. All solvents were removed under vacuum to give crude 2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carbonitrile. LCMS: m/z 252.15 (M+H)+, 0.78 min (method 7).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH:31][C:13]([C:10]2[CH:11]=[C:12]3[C:7]([CH:6]=[N:5][N:4]3[CH:1]([CH3:2])[CH3:3])=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:9]=2)=[O:15])=[N:28][CH:29]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc3c2cnn3C(C)C)nc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC#N
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc3c2cnn3C(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (0.24 g, 0.814 mmol) in acetonitril was added C-(5-methyl-pyrazin-2-yl)-methylamine (0.12 g, 0.976 mmol), EDCI (0.23 g, 1.22 mmol), HOBt (0.16 g, 1.22 mmol), and NMM (0.45 mL, 4.07 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gave 0.144 g (44%) of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide MS (M+H)=401.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=1.[H][H]>[C].[Pd].CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1
Reactant: [H][H]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Yield: 84.6 %

Procedure:
A solution of 8.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-nitrobenzamide and 0.8 g of 10% palladium carbon added to 50 ml of methanol was stirred in a hydrogen atmosphere at room temperature. After disappearance of the starting raw material was confirmed by means of TLC, the reaction solution was filtered and the obtained filtrate was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent (development solvent; hexane:ethyl acetate=3:1) to obtain 6.3 g of the desired product (Yield: 85%) in the form of powder.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH3:10])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][N:13]([CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])[S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH3:10])=[CH:27][CH:28]=1
Reactant: CN(C)CCO
Reactant: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCN(CCN(C)CC=Cc1ccc(Cl)cc1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 1.0 g of the amorphous compound obtained in Example 190, 0.267 g of 2-dimethylamino ethanol and 0.982 g of triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a solution of 0.652 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. After 2 hours, the reaction mixture was concentrated under a reduced pressure to remove tetrahydrofuran, and resulting residue was dissolved in 10 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid. The aqueous layer was alkalized with sodium bicarbonate and extracted three times with 10 ml of ethyl acetate, and the organic layer was dried over magnesium sulfate and evaporated to removed the solvent under a reduced pressure. The resulting residue was then applied to a silica gel column and eluted with 3% methanol in chloroform, to obtain 0.77 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCc1cccs1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CC(OCc3cccs3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-diphenylmethylazetidin-3-ol (359 mg, 1.5 mmol) in DMF (1 mL) at 0° C. under nitrogen was added NaH (60% in oil, 66 mg, 1.65 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with 2-(chloromethyl)thiophene (464 mg, 3.5 mmol; which may be prepared as described in Step 1) dissolved in DMF (2 mL).
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27].[SH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[C:7]([S:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[C:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:27])([F:28])[F:29]
Reactant: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2F)cc1
Reactant: O=C(O)c1ccc(S)cc1
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Sc2ccc(C(=O)O)cc2)cc1

Procedure:
(R)-N-{2-Chloro-3-fluoro-4-[4-(N,N-dimethylcarbamoyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 18) was treated with 4-mercaptobenzoic acid according to the procedure of Example 50 to yield the title compound as a white solid.(0.39 g, 25%). NMR: 1.60 (s, 3H), 2.90 (s, 3H), 3.00 (s, 3H), 7.55-7.65 (m, 4H); 7.90-7.95 (m, 4H), 8.05 (s, 1H), 8.55 (d, 1H), 8.65 (d, 1H), 9.95 (s, 1H); 10.60 (s, 1H); m/z: 629.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10]([CH2:19]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:27])CC)C.O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10]([CH2:19][F:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](c2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](CF)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 112.5 %

Procedure:
1.5 g trans-3-hydroxymethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.41 mmol) were dissolved in 20 ml dichloromethane and 1.31 g of diethylaminosulfurtrifluoride (DAST, 8.1 mmol) in 2 ml dichloromethane were added at 0° C. The reaction mixture was stirred for 72 h at room temperature, further dichloromethane and water were added, the organic phase was separated, dried over magnesium sulphate, filtered and evaporated to dryness to yield 1.7 g of a light yellowish oil. The crude product was purified via silica gel chromatography using n-heptane/ethyl acetate (6:4) as eluent to yield 1.08 g product.
Reaction SMILES: II.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=O)[CH3:20])[CH2:11][CH2:10]1.[NH2:22][C:23]([NH2:25])=[S:24]>O>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[N:22]=[C:23]([NH2:25])[S:24][CH:20]=2)[CH2:11][CH2:10]1
Reactant: NC(N)=S
Reactant: CC(=O)CCCCN1CCN(c2ncccn2)CC1
Agent: II
Solvent: O
Product: Nc1nc(CCCCN2CCN(c3ncccn3)CC2)cs1
Temperature: 110 °C

Procedure:
Iodine, 6.34 g, is added in small portions to a mixture of 6 g of 6-[4-(2-pyrimidinyl)-1-piperazinyl]-2-hexanone (Example A) and 3.8 g of thiourea. The resulting paste is heated at 110° C. overnight. The mixture is taken up into boiling water, filtered, and basified with ammonium hydroxide. Dichloromethane is used to extract the products which are purified by silica gel chromatography to afford 2 g of recovered starting ketone, 0.8 g of 4-methyl-5-[3-[4-(2-pyrimidinyl)-1-piperazinyl]propyl]-2-thiazolamine (Example 1); mp 152°-156° C.; and 1.2 g of 4-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2-thiazolamine (Example 1a); mp 101°-104° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=[N:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O=P(Cl)(Cl)Cl>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(C=NO)o2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: N#Cc1ccc(-c2ccc(C#N)o2)cc1
Yield: 68.7 %

Procedure:
A stirred mixture of 5-(4-cyanophenyl)-2-furaldehyde oxime (16 g, 0.075 mole) and benzene (400 ml) was heated to reflux and a solution of POCl3 (4 ml) in benzene (20 ml) was added dropwise over 15 minutes. The mixture was refluxed for 11/2 hours and filtered while hot. The filtrate was washed with 5% NaHCO3 (500 ml), H2O (500 ml), dried over MgSO4 and Darco and filtered. The filtrate was stripped of solvent under reduced pressure to yield 10 g (69%) of 5-(4-cyanophenyl)-2-furonitrile.
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[N+:27]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:27]([C:30]1[CH:31]=[C:32]([NH:36][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CCC(=O)Nc2cccc([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (402 mg, 2.10 mmol) and Et3N (2934, 2.10 mmol) in anhydrous DCM (17 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (480 mg, 2.00 mmol) and DMAP (24 mg, 0.20 mmol) and stir the resulting solution for 5 min. 3-Nitro-phenylamine (88) (414 mg, 3.00 mmol) and stir the reaction solution 24 h at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with EtOAc (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain N-(3-Nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propionamide (89) (508 mg, 70%) as a yellow solid. 1H NMR (400 MHz, CDCl3): 2.65 (t, 2H, J=7.5 Hz); 2.98 (t, 2H, J=7.5 Hz); 3.79 (s, 6H); 3.81 (s, 3H); 6.42 (s, 2H); 7.41 (s, 1H); 7.45 (t, 1H, J=8.3 Hz); 7.84 (d, 1H, J=8.3 Hz); 7.92 (d, 1H, J=8.3 Hz); 8.31 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@:13]([OH:27])([CH3:26])[CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1.CN>C(O)C.CO>[NH2:15][CH2:14][C@@:13]([CH3:26])([OH:27])[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: C[C@](O)(CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)CN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Solvent: CO
Product: C[C@@](O)(CN)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a solution of 2-[(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (278 mg, 0.6 mmoles) in ethanol (5 ml) was added aqueous methylamine (40% wt. solution in water, 6 ml). The mixture was stirred at room temperature for 24 h and then concentrated in vacuo to leave a crude yellow glass. This glass was dissolved in methanol (2 ml), added to an Isolute Flash SCX cartridge (2 g), washed with methanol (25 ml) and 7N ammonia in methanol (25 ml). The methanolic ammonia was concentrated in vacuo to give the title compound as a yellow glass (165 mg).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:34][CH:33]=2)[S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])[CH:27]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(O)c2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(OCC(=O)OC(C)(C)C)c2)n1
Reaction time: 16 h
Yield: 82.8 %

Procedure:
tert-Butyl bromoacetate (87.3 μl, 0.596 mmol) was added to a stirred solution of 1-methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-hydroxy-phenyl)-amide (150 mg, 0.40 mmol) and cesium carbonate (388 mg, 1.19 mmol) in anhydrous dimethyl formamide (10 ml) and then stirred at ambient for 16 hours. The reaction was diluted with ethyl acetate (10 ml), washed with water (3×20 ml) and the organic extracts were concentrated in vacuo to obtain crude product. The residue was purified by flash chromatography eluting with 10% methanol/dichloromethane to yield a yellow oil (163 mg, 56% yield). HPLC retention time 6.47 min Mass spectrum (ES+) m/z 509 (M+H).
Reaction SMILES: OS(O)(=O)=O.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]1>>[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=S(=O)(O)O
Product: O=C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2% H2SO4 and ethyl 4-oxo-cyclohexanoate 46 (10.0 g., 58.7 mmole) was stirred vigorously at 80° for 2 hours. The solution was cooled to r.t. and decanted. The supernatant was extracted with ether (3×150 mL.) and the combined organic layers dried over Na2SO4 and evaporated to dryness. The pale yellow residue was stirred with warm 30% ethyl acetate in hexane (200 mL.) and filtered. The title compound (3.5 g.) precipitated from the filtrate upon cooling. MS (M+H)+ 143.2
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>O=[Mn]=O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:15]1[CH:14]=[C:13]([C:2](=[O:1])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(NCCCCCO)c1
Agent: O=[Mn]=O
Product: CC(C)(C)OC(=O)NCCC(=O)c1cccc(NCCCCCO)c1

Procedure:
MnO2 oxidation of tert-butyl 3-hydroxy-3-(3-(5-hydroxypentylamino)phenyl)propylcarbamate following the method used in Example 12 gives tert-butyl 3-(3-(5-hydroxypentylamino)phenyl)-3-oxopropylcarbamate.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:26]1.[I-].[Na+]>CN(C)C=O>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:38][CH2:39]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C
Yield: 26.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g), triethylamine (3 cc) and 4-(1,2-benzisoxazol-3-yl)piperazine (4 g) and sodium iodide (3 g) in dimethylformamide (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (22 cc), 2-{2-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g) is obtained, m.p. 148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:6]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)=[O:28])[CH:22]=1.O>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([N:17]4[CH2:18][CH2:19][CH:14]([C:7]5[C:8](=[O:13])[NH:9][C:10]6[C:5]([CH:6]=5)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=6)[CH2:15][CH2:16]4)[CH:22]=3)=[O:28])=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)c(C3CCN(c4cc(C(=O)c5cc(C)c6c(c5)oc(=O)n6C)ncn4)CC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 mg (0.087 mmol) 6-methoxy-3-piperidin-4-yl-1H-quinoline-2-one, 30 mg (0.10 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 50 μl (0.36 mmol) TEA were combined in 3 mL DMF and stirred overnight at RT. Then the reaction mixture was added to water, the precipitate formed was suction filtered and washed with MeOH. Next, the precipitate was boiled in DMF/MeOH and the precipitate was suction filtered.