Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(COC)OC.O.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.[Pd]>[C:30]([NH:33][C:34]1[CH:39]=[C:38]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:3]=2[CH3:29])[CH:37]=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Temperature: 150 °C
Yield: 85.8 %

Procedure:
A solution of N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (321 mg, 0.7 mmol) obtained in Example 35, (3-(acetylamino)phenyl)boronic acid (188 mg, 0.7 mmol), palladium(0) tetrakis(triphenylphosphine) (40.5 mg, 0.035 mmol), and an aqueous 2 N sodium carbonate solution (1.05 mL) in dimethoxyethane (2.1 mL)-ethanol (0.7 mL) was reacted with heating at 150° C. for 5 minutes in a microwave reactor. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The filtrate was washed with saturated brine and dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 308 mg (yield: 86%) of the title compound. Melting point: 247-248° C. (ethyl acetate-hexane).
Reaction SMILES: ClC1SC=C(C)C=1NC([NH:10][CH:11]1[CH2:20][CH2:19][CH2:18][CH2:17][C:12]21[O:16][CH2:15][CH2:14][O:13]2)=N>Cl.O>[O:13]1[C:12]2([CH2:17][CH2:18][CH2:19][CH2:20][CH:11]2[NH2:10])[O:16][CH2:15][CH2:14]1
Reactant: Cc1csc(Cl)c1NC(=N)NC1CCCCC12OCCO2
Agent: Cl
Solvent: O
Product: NC1CCCCC12OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 192.3 %

Procedure:
N-(2-Chloro-4-methylthiophen-3-yl)-N′-(1,4-dioxaspiro[4.5]dec-6-yl)guanidine (24 mg) was dissolved in 2N hydrochloric acid (1 ml) and stirred at room temperature for 30 min. Concentrated hydrochloric acid (1 ml) was then added, and the mixture was stirred for another two hours. The mixture was then diluted with a little water and freeze-dried. Toluene was added to the residue and then distilled off under reduced pressure. This step was repeated twice, giving 22 mg of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(methyloxy)ethanamine using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.29 (1H, b), 8.54 (1H, s), 8.26 (1H, s), 7.24 (2H, dd, J=6, 9 Hz), 6.99 (2H, t, J=9 Hz), 4.39 (2H, t, J=8 Hz), 4.15 (2H, s), 3.50-3.69 (6H, m), 3.42 (3H, s), 3.36 (2H, b), 2.36 (2H, b), 1.75 (4H, b); ES+ MS: 497 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.C(C(CC)=O)C.[Na+].[Cl-]>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]#[C:10][CH3:11])[CH2:12][C:13]([OH:21])=[O:14])=[CH:6][CH:7]=1
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(=O)CC
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(O)cc1
Yield: 77.5 %

Procedure:
A 1 L round bottom flask was charged with compound 1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated to reflux for 48 hours. After cooling, the aqueous layer was saturated with NaCl(s) and separated. The organic layer was dried over MgSO4, filtered, and concentrated to a light brown oil which was crystallized from hot EtOAc:hexanes (1:2). After collecting and drying, the product was obtained as an off-white powder (20.3 g). 1H NMR (500 MHz, DMSO-d6) δ 12.2 (s, 1H); 9.27 (s, 1H); 7.12 (d, 2H, J=8.5 Hz); 6.67 (d, 2H, J=8.6 Hz); 3.87 (m, 1H); 2.54 (m, 2H); 1.82 (d, 3H, J=2.4 Hz). MS ESI (pos.) m/e: 205.1 (M+H); 227.1 (M+Na).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[CH2:22][CH2:23][O:24][NH2:25])([O-:3])=[O:2].ClC1C=C(C(F)(F)F)C=CC=1OC1C=CC([N+]([O-])=O)=C([N+]([O-])=O)C=1.Cl.C(ON)C.C1(CCON)C=CC=CC=1.Br[CH2:66][C:67]([O:69][CH3:70])=[O:68]>>[CH3:70][O:69][C:67]([CH2:66][NH:25][O:24][CH2:23][CH2:22][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:68]
Reactant: NOCCc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)CBr
Agent: CCON
Agent: Cl
Agent: NOCCc1ccccc1
Product: COC(=O)CNOCCc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 29, N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]ethoxyamine is prepared from 4-(2-chloro-4-trifluoromethylphenoxy)1,2-dinitrobenzene and ethoxyamine hydrochloride. The resulting N-phenylethoxyamine is then reacted with methyl bromoacetate, following the methods of this example, to yield N-methoxycarbonylmethyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]ethoxyamine.
Reaction SMILES: [H-].[Na+].CI.[Br:5][C:6]1[CH:11]=[N:10][C:9]2[N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:8]=2C=1N.[CH3:26][N:27]([CH3:30])[CH:28]=O>>[Br:5][C:6]1[CH:11]=[N:10][C:9]2[N:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:8]=2[C:28]=1[N:27]([CH3:30])[CH3:26]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(Br)cnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C)c(Br)cnc32)cc1
Reaction time: 2 h

Procedure:
55% Sodium hydride (19 mg) and methyl iodide (0.027 ml) were added to a solution of the compound obtained in Step 2 of Example 130 (64 mg) in N,N-dimethylformamide (3.6 ml) in an ice bath, and the mixture was stirred in an ice bath for 2 hours. The reaction solution was separated by adding an aqueous ammonium chloride solution and ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (73 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CS(=O)(=O)c1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and (3-methylsulfonylphenyl)methanamine (22.0 mg, 0.12 mmol). The title compound was obtained as a solid (22.8 mg, 44% yield). MS m/z: 517.95, 519.95 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[K+]>[SiH](CC)(CC)CC.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][CH2:8][OH:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A mixture of 2.5 g (15 mmol) of 4-fluorocinnamic acid and 0.06 g of (PPh3)3RhCl (Wilkinson's catalyst) in 5 mL of Et3SiH was heated at 100° C. for 3 h. The reaction mixture was cooled to rt, and to it was added 20 mL of THF and 30 mL (30 mmol) of LiAlH4 (1 M in THF) and the reaction mixture was stirred at 40° C. for 3 h. The reaction mixture was cooled to rt and to it was successively added 3 mL of H2O, 3 mL of 15% KOH solution and 3 mL of H2O. The reaction mixture was filtered and the Al-salts were washed with ethyl acetate. The combined organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 4:1) to give 2.26 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[CH2:29]([NH2:31])[CH3:30].O>C1COCC1>[CH2:29]([NH:31][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1)[CH3:30]
Reactant: CCN
Reactant: N#Cc1c(Cl)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(OCc2ccccc2)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
30 mg (0.08 mmol) of 2-chloro-4-(1,3-benzodioxol-5-yl)-6-benzyloxy-3,5-pyridinedicarbonitrile (example 4, step 1) and 10.4 mg (0.23 mmol) of ethylamine are shaken together in 0.12 ml of THF for about 16 h. Water is added to the reaction solution and the product that crystallizes out is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S(=O)(=O)(O)[O-].[Na+]>ClCCl>[Br:16][C:7]1[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH:8]=1
Reactant: BrBr
Reactant: Clc1ccc2sccc2c1
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc2scc(Br)c2c1
Yield: 85.2 %

Procedure:
In a 250 mL 2-neck round flask, 5-chlorobenzothiophene (2 g, 11.8 mmol) was dissolved in dichloromethane (10 mL), and sodium acetate (NaOAc) (1.95 g, 23.6 mmol) and Br2 (1.89 g, 11.8 mmol) were gradually added to the mixture for 5 minutes at 0□. After the reaction, a 10% sodium bisulfate (NaHSO3) solution (20 mL) was poured to the mixture, and then the resulting mixture was extracted with ethyl acetate (20 mL), dried over MgSO4, and distilled in vacuum to give 2.49 g of yellow solid (85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]([CH3:24])[CH3:23])[C:10]=2[N:9]=1.[C:25](Cl)(=[O:27])[CH3:26].C(O)(C(F)(F)F)=O>>[CH2:20]([C@H:12]1[N:11]([CH:22]([CH3:23])[CH3:24])[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:25](=[O:27])[CH3:26])[N:17]=[CH:16][C:15]=2[N:14]([CH3:18])[C:13]1=[O:19])[CH3:21]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C(C)C
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(C)=O)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-aminopyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 93) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with acetyl chloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 369.1 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 9.71 (s, 1H), 8.43 (d, 1H, J=5.0 Hz), 8.27 (d, 1H, J=5.0 Hz), 8.25 (s, 1H), 4.59 (m, 1H), 4.49 (m, 1H), 3.38 (s, 3H), 2.26 (s, 3H), 1.92 (m, 1H), 1.80 (m, 1H), 1.47 (t, 6H, J=6 Hz), 0.81 (t, 3H, J=7.5 Hz).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([NH:32][CH2:33][CH2:34][CH2:35][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)=[O:29])=[CH:30][CH:31]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)COc1ccc(OCc2ccccc2)cc1
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(COc1ccc(OCc2ccccc2)cc1)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1'-Carbonyldiimidazole (16.2 g) was added to a stirred suspension of 4-benzyloxyphenoxyacetic acid (25.8 g) in dry THF (350 ml) and the mixture was stirred at ambient temperature for 2 hours. 1-(3-Aminopropyl)imidazole (12.5 g) was added and the mixture was stirred for a further 18 hours. The mixture was filtered and the filtrate evaporated to give a residue which was treated as in Example 9a to give 2-(4-benzyloxyphenoxy)-N-[3-(imidazol-1-yl)propyl] acetamide m.p. 112°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37]([O:19][CH2:18][CH:17]([C:16]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[C:10]4[C:15]=3[CH2:14][CH2:13][CH2:12][CH2:11]4)[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29]
Reactant: COC(=O)C1(Oc2ccc(O)cc2)CC1
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc(OCC(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 29.2, [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanol (example 37.1) was reacted with 1-(4-hydroxy-phenoxy)-cyclopropanecarboxylic acid methyl ester (Hazeldine, Stuart T.; Polin, Lisa; Kushner, Juiwanna; White, Kathryn; Corbett, Thomas H.; Horwitz, Jerome P. Bioorganic & Medicinal Chemistry (2005), 13(12), 3910-3920) in the presence of tri-n-butylphosphine and N,N,N′,N′-tetramethylazodicarboxamide in THF at ambient temperature to give the title compound as white solid. MS: m/e=549.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][S:10]([CH3:12])=O)=[C:4]([NH:14][CH3:15])[CH:3]=1.S([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][S:10][CH3:12])=[C:4]([NH:14][CH3:15])[CH:3]=1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CNc1cc(F)ccc1C(=O)CSC
Reaction time: 72 h

Procedure:
A mixture of 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (100 g), prepared in a similar manner to that described in Example 1, sodium hydrogen sulphite (1 kg) and water (2.5 1) was stirred under nitrogen and heated at 90°-105° for 3 hours. The mixture, was allowed to cool and then stood at ambient temperature for 72 hours. The mixture was extracted with dichloromethane (3×250 ml) and the combined extracts evaporated to give a solid product. Crystallisation from hexane gave 1-(4-fluoro-2-methylaminophenyl)-2-(methylthio)ethanone, m.p. 61.5°-63°.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:29][C@@H:30]2[C:36](=[O:37])[N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:34]3[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=3[O:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:24]([C@@H:23]([NH:29][C@@H:30]1[C:36](=[O:37])[N:35]([CH2:38][C:39]([OH:41])=[O:40])[C:34]2[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=2[O:32][CH2:31]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:26])=[O:25]
Reactant: CCOC(=O)[C@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of tert-butyl 3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic acid (1.5 ml) is added 30% hydrogen bromide-acetic acid solution (1.5 ml). The resulting mixture is allowed to stand for 0.5 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (10 ml). The solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2 ml), the mixture is chromatographed on MCI gel using water-methanol (1:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(S)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.15 g) as colorless powder.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[C:23]([NH2:29])=[C:22]([CH3:30])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][C:20]3[CH:21]=[C:22]([CH3:30])[C:23]([NH2:29])=[C:24]([NH2:26])[CH:25]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c([N+](=O)[O-])c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 3.5 h

Procedure:
A suspension of 2.00 g (3.24 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 300 mg 10% Pd/C in 100 mL MeOH was hydrogenated for 3.5 h at 50° C. and 50 psi hydrogen pressure. The catalyst was filtered off, the filtrate was evaporated down i. vac. and the residue was purified by chromatography (silica gel, gradient DCM/MeOH 30:1 to DCM/MeOH 15:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CN1CCNCC1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN1CCN(CCCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 1-Methylpiperazine were converted to yield 3-(4-Bromo-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzo[d]isothiazole as white solid, MS: 460 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[N:11][OH:12])[CH2:3]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CCCC(=NO)C1

Procedure:
To a mixture of 3,3-dimethylcyclohexanone (4.0 g, 0.032 mol) and hydroxylamine hydrochloride (2.9 g, 0.041 mol) in ethanol (20 mL) was added dropwise a solution of sodium carbonate (4.3 g, 0.041 mol) in water (25 mL). The mixture was heated at reflux for 3 hours. The mixture was concentrated in vacuo to remove the ethanol and the aqueous residue was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 3,3-dimethylcyclohexanone oxime as a yellow oil. This material was used without further purification.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6]O.C([O-])(O)=O.[Na+].[F:13][CH2:14][C:15]([CH2:22][F:23])([CH3:21])[C:16](=[O:20])[CH2:17][C:18]#[N:19].Cl>CO.O>[F:13][CH2:14][C:15]([C:16]1[O:20][N:19]=[C:18]([NH2:6])[CH:17]=1)([CH3:21])[CH2:22][F:23]
Reactant: NO
Reactant: CC(CF)(CF)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CC(CF)(CF)c1cc(N)no1
Temperature: 60 °C
Yield: 54.7 %

Procedure:
To a mixture of hydroxylamine sulfate (0.59 g, 3.6 mmol) and NaHCO3 (0.700 g, 8.3 mmol) in MeOH (1 mL) and water (10 mL) was added 5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile (0.483 g, 3 mmol). After heated at 60° C. for 8 hours, to it was added 10% HCl until pH 1. It was heated at 60° C. for 3 hours, basified with saturated NaHCO3, and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-amine as needles (0.289 g, 55%). 1H NMR (300 MHz, CDCl3) δ 5.76 (s, 1H), 4.59 (q, 2H), 4.50 (q and br, 4H), 1.37 (s, 3H); LC-MS (ESI) m/z 177 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH:24]=[CH:25]1)[C@@H:20]([CH3:33])[CH2:19]3.O[C@H:35]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)C=C1)CC3>>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH2:24][C@@H:25]1[CH3:35])[C@@H:20]([CH3:33])[CH2:19]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43CO)[C@@H]1CC[C@@H]2O
Reactant: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(CO)C=CC(=O)C=C12
Solvent: CCC(=O)O
Product: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@]2(CO)C1=CC(=O)C[C@@H]2C

Procedure:
Substituting 17β,19-dihydroxy-17α-methyl-1,4-androstadien-3-one dipropionate and 17β,19-dihydroxy-6α-methyl-1,4-androstadien-3-one dipropionate for 17β,19-dihydroxy-1,4-androstadien-3-one in the above procedure results in the formation of 17β,19-dihydroxy-1α,17α-dimethyl-4-androsten-3-one dipropionate and 17β,19-dihydroxy-1α,6α-dimethyl-4-androsten-3-one dipropionate.