Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[C:10]([OH:20])(=O)[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].O.[OH:22]N1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:20])[CH:11]([OH:12])[C:13]2[CH:18]=[CH:17][C:16]([OH:22])=[CH:15][CH:14]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(O)c1ccccc1
Reactant: Cc1cc(C)cc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)C(O)c2ccc(O)cc2)c1
Reaction time: 16 h

Procedure:
To a stirring solution of 3,5-dimethylaniline (5.0 g, 41.3 mmol), mandelic acid (7.69 g, 41.3 mmol) and 1-hydroxybenzotriazole hydrate (6.14 g, 45.5 mmol) in dimethylformamide (100 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.73 g, 45.5 mmol) under nitrogen at room temperature. After stirring further for 16 hr, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with 10% potassium hydrogen sulfate (2×50 mL), brine (50 mL), saturated sodium hydrogen carbonate (2×50 mL) and brine (50 mL). The organic phase was dried (MgSO4) and evaporated to give the product N-(3,5-Dimethyl-phenyl)-2-hydroxy-2-(4-hydroxy-phenyl) acetamide in 9.3 g yield.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[CH:13]=1)([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].C([O-])(=O)C.[Na+].[N:26]#[C:27]Br.CCCCCC>C(O)C.C(OCC)(=O)C>[Br:20][C:16]1[CH:15]=[C:14]([N:12]2[CH:13]=[C:9]([C@:2]([NH2:1])([CH3:8])[C:3]([F:6])([F:7])[CH2:4][O:5][C:27]#[N:26])[CH:10]=[N:11]2)[CH:19]=[CH:18][CH:17]=1
Reactant: N#CBr
Reactant: C[C@@](N)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)CO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@](N)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)COC#N
Temperature: 40 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
A solution of (R)-3-amino-3-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-butan-1-ol (5.1 g, 14.73 mmol) and sodium acetate (3.62 g, 44.2 mmol) in ethanol (90 ml) was warmed to 40° C. Cyanogen bromide (1.71 g, 16.21 mmol) was added and the mixture allowed to stir at 40° C. for 16 hours. Removal of the solvent at reduced pressure followed by purification of the resultant crude material by column chromatography on silica gel using a 3:2-mixture of hexane and ethyl acetate as the eluent yielded the (R)-1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-3-cyanato-2,2-difluoro-1-methyl-propylamine (3.2 g, 58% yield) as a colorless sticky solid. MS (ISP): m/z=369.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:10]1[S:41][C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:20]=3[O:21][C@@H:22]3[CH2:26][N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C@H:24]([CH2:31][O:32]C(=O)C)[CH2:23]3)[C:12]=2[C:11]=1[CH3:42])(=[O:9])[NH2:8].OS([O-])(=O)=O.[K+]>CO.C1COCC1>[F:40][C:37]1[CH:38]=[CH:39][C:19]([NH:18][C:17]2[C:12]3[C:11]([CH3:42])=[C:10]([C:7]([NH2:8])=[O:9])[S:41][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:20]([O:21][C@H:22]2[CH2:23][C@@H:24]([CH2:31][OH:32])[N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:26]2)[CH:36]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CN1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(S(C)(=O)=O)C3)c12
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Potassium carbonate (278 mg) was added to a solution of acetic acid (2S,4S)-4-[2-(6-carbamoyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-5-fluoro-phenoxy]-1-methanesulfonyl-pyrrolidin-2-ylmethyl ester (360 mg) in MeOH (5 ml) and THF (2 ml). The reaction was stirred at room temperature for 90 h. 10% aq. KHSO4 was added and the resultant suspension was filtered. The filter cake was washed with dichloromethan and diethylether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=O)[CH2:8][C:7]=2[CH:13]=1.[CH2:14]([NH:17][CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9]3[N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20](=[O:21])[C:8]=3[C:7]=2[CH:13]=1
Reactant: CCCNCCC(=O)OC
Reactant: COc1ccc2c(c1)CC(=O)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCN1CCC(=O)C2=C1COc1ccc(OC)cc12

Procedure:
A mixture of 8.9 g of 6-methoxy-2H-[1]-benzopyran-3-one, 7.46 g of methyl 3-(propylamino)-propionate, 0.8 ml of trifluoroacetic acid in 80 ml toluene is refluxed for 7 hours in a Dean Stark apparatus; additional 0.8 ml portions of trifluoroacetic acid are added at 2, 4 and 6 hours. The reaction mixture is cooled and the solvent is removed in vacuo. The residue is crystallized from ether/methanol to afford 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridin-1-one, m.p. 97°-100°.
Reaction SMILES: CO[C:3](=[NH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=O>CO.O>[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][N:21]2[C:22](=[O:27])[CH:23]=[C:24]([CH3:26])[N:11]=[C:3]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[OH:10])[CH:16]=[CH:17][CH:18]=1
Reactant: NCCc1cccc(F)c1
Reactant: COC(=N)c1ccccc1O
Reactant: COC(=O)CC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(=O)n(CCc2cccc(F)c2)c(-c2ccccc2O)n1
Yield: 10 %

Procedure:
Utilizing the methods described in Example 1 the title compound was prepared from 2-hydroxy-benzimidic acid methyl ester (500 mg, 2.67 mmol), 2-(3-fluoro-phenyl)-ethylamine (330 μl, 2.6 mmol) and methyl acetoacetate (3.0 mL) yielding 160 mg (10%) of 3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one as a white solid after two purifications by flash chromatography on ODS silica gel eluting with methanol-water (4.5:6.5) followed by recrystallization from a large volume of toluene (100 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:21][CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:23][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:12][CH2:11][C:6]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(CCCO)CC3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CCCO)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol (1000 mg, 4.0983 mmol) in DMF (10 mL) was portionwise added sodium hydride (491.8 mg, 12.25 mmol). After stirring at RT for 5 min, 4-(oxiran-2-yl)pyridine (620 mg, 4.92 mmol) was added dropwise into the reaction mixture, which was stirred at RT overnight. Ice water was added into the reaction mixture and the solid mass filtered, washed with water (2×10 mL) and hexane (2×50 mL). The residue was purified by reverse phase HPLC to yield 3-(3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol. 1H NMR (CD3OD, formate salt) δ (ppm): 8.43 (bs, 2H), 7.39 (d, 2H), 7.23 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 5.07 (t, 1H), 4.48 (bs, 2H), 4.23 (m, 2H), 3.7 (t, 2H), 3.6 (bs, 2H), 3.4 (t, 2H), 3.2 (m, 1H), 2.95-3.03 (m, 1H), 2.4 (s, 3H), 2.03 (bs, 2H). Separation by chiral HPLC provides enantiomers II-75a-b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)O)[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[ClH:1].[Cl:38][C:18]([C:26]1[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=1)([C:20]1[N:24]([CH3:25])[CH:23]=[N:22][N:21]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]1[N:33]=[N:34][N:35]=[C:10]1[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1cnnc1C(O)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Reactant: O=S(Cl)Cl
Product: Cl
Product: Cn1cnnc1C(Cl)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(3chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanol (0.0076 mol) in thionyl chloride (50 ml) was stirred at 65° C. for 4 hours, then cooled and the solvent was evaporated till dryness. The residue was taken up twice with DCM. The solvent was evaporated, yielding 7-[chloro(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline monohydrochloride. This product was used directly in the next reaction step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Br)ccc1O
Yield: 58.2 %

Procedure:
Using 5-bromosalicylic acid and 3,4-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]O)=[CH:26][C:25]=1[O:34][CH3:35])(=[O:22])[CH3:21].C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][Br:37])=[CH:26][C:25]=1[O:34][CH3:35])(=[O:22])[CH3:21]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OCCO)ccc1OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OCCBr)ccc1OC(C)=O
Reaction time: 5 h

Procedure:
A solution of triphenylphosphine (0.123 mL, 0.530 mmol) in dry CH2Cl2 (1.3 mL) was added dropwise via cannula to a stirred solution of 4-(2-hydroxyethoxy)-2-methoxyphenyl acetate (100 mg, 0.442 mmol) and carbon tetrabromide (0.051 mL, 0.530 mmol) in dry CH2Cl2 (3.0 mL) at 0° C. under N2. After 5 h at 0° C., the reaction mixture was concentrated in vacuo and the residue obtained was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 1125 mL) to afford 4-(2-bromoethoxy)-2-methoxyphenyl acetate, as a colorless oil. Rf=0.78 (50% EtOAc/hexanes). LCMS calc.=289.1; found=288.8 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 6.93 (d, J=8.7 Hz, 1 H); 6.57 (d, J=2.8 Hz, 1 H); 6.42 (dd, J=8.7, 2.8 Hz, 1 H); 4.26 (t, J=6.2 Hz, 2 H); 3.80 (s, 3 H); 3.62 (t, J=6.2 Hz, 2 H); 2.29 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH2:26][CH2:27][CH3:28])C(OCC(Cl)(Cl)Cl)=O)[C:14]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[CH:31][CH:30]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.O1CCCC1.C(O)(=O)C>[Zn].CO>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:26][CH2:27][CH3:28])[C:14]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[CH:33][CH:34]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reaction time: 2 h

Procedure:
To 22 g (35 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propyl-N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5,-dihydro-1H-pyrazole-1-carboxamide (Example 585) was added 100 ml of tetrahydrofuran, 100 ml of methanol, 4.6 g (70 mmole) of zinc dust, and finally 6.4 g (106 mmole) of acetic acid. After stirring for 2 hours, the starting material had been consumed as shown by TLC. The mixture was filtered from unreacted zinc, concentrated in vacuo, dissolved in 200 ml of diethyl ether, washed twice with 100 ml of water, washed once with 100 ml of dilute aqueous sodium hydroxide and washed once with brine. The resulting ether solution was dried over anhydrous magnesium sulfate, concentrated in vacuo, and chromatographed over silica gel using hexanes, diethyl ether, and ethyl acetate yielding 1 g of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propyl-N-(2,2-dichloroethoxycarbonyl)-amino)-4,5,-dihydro-1H-pyrazole-1-carboxamide and 12 g of the desired compound, mp 130°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:70])[CH:65]1[CH2:69][CH2:68][NH:67][CH2:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH:65]([N:64]([CH3:70])[CH3:63])[CH2:66]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C1CCNC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(N(C)C)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-dimethylamino-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[CH:13][N:14]([CH3:16])C)[C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23]C(N)=[CH:21][CH:20]=1>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[CH:13][NH:14][C:16]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=C1C(=O)NCc2cc(Br)ccc21
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC=C2C(=O)NCc3cc(Br)ccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 22.2 %

Procedure:
To a suspension of crude 7-bromo-4-dimethylaminomethylene-1,4-dihydro-2H-isoquinolin-3-one (400 mg, 1.43 mmol) in N,N-dimethylformamide (250 mL) is added 4-anisidine (193 mg, 1.57 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. The reaction mixture is filtered and the filtrate is purified by Prep. HPLC. The pure fractions were combined and concentrated to yield 114 mg of 7-Bromo-4-[(4-methoxy-phenylamino)-methylene]-1,4-dihydro-2H-isoquinolin-3-one.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[ClH:14].[N+](N([N+]([O-])=O)C1C=CC=CC=1)([O-])=O.ClCl>O>[Cl:14][C:7]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[NH2:6]
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: ClCl
Agent: O=[N+]([O-])N(c1ccccc1)[N+](=O)[O-]
Solvent: O
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 94 %

Procedure:
183 parts of 2,4-dinitroaniline are suspended in 220 parts of water and the suspension is ground. 800 parts of 14.2 % hydrochloric acid are charged to a reactor. The hydrochloric acid may originate from a previous batch and, after isolation of the product, is recycled to the reactor. The aqueous suspension of dinitroaniline and a total of 78 parts of chlorine are then added simultaneously to the hydrochloric acid over 240 minutes, with the addition of dinitroaniline being made over 240 minutes, whereas the chlorine is added for a further 20 minutes, i.e. over a total time of 260 minutes. The batch is allowed to react for 30 minutes and excess chlorine is expelled over a further 30 minutes. The product is then isolated by filtration, washed until neutral and dried, affording 204 parts of 2-chloro-4,6-dinitroaniline, corresponding to a yield of 94 %. Melting point: 157.5° C. (lit. : 157°-159° C.). Analysis of gas chromatography shows that the product has the same retention time as authentic material. Comparable results are obtained by carrying out the reaction at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:40])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([OH:28])=O)[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:7]=1.Cl.[CH3:42][NH2:43]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:40])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([NH:43][CH3:42])=[O:28])[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[CH:36][CH:37]=2)[CH:7]=1
Reactant: CN
Reactant: COc1ncc(CC(=O)O)cc1-c1nc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)Cc1cnc(OC)c(-c2nc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(Cl)ccc2C)C3=O)c1

Procedure:
The title compound was prepared in analogy to the procedure described for example 147 but using the product from example 146 and methylamine hydrochloride. tR: 0.97 min (LC-MS 2); ESI-MS: 569.3/571.3 [M+H]+ (LC-MS 2); Rf=0.15 (CH2Cl2/MeOH, 20:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2].[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([N:24]2[CH2:25][CH2:26][CH:22]([NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[CH2:23]2)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 70.1 %

Procedure:
A solution of 2,3,4-trifluorobenzoic acid ethyl ester (Example 1g, 3.70 g, 18.1 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under nitrogen atmosphere for 4.5 hours. The solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and the mixture concentrated in vacuo. The resulting residue is then purified by column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (4.70 g). 1H NMR (CDCl3): δ 7.59–7.49 (m, 1H), 6.35–6.26 (m, 1H), 4.88–4.84 (bd, 1H), 4.39–4.28 (m, 3H), 3.81–3.50 (m, 3H), 3.48–3.34 (m, 1H), 2.32–2.15 (m, 1H), 2.02–1.76 (m, 1H), 1.45 (s, 9H), 1.40 (t, 3H).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:12])([F:11])[C:6]([O:8]CC)=O.[C:13]([C:16]1[S:17][C:18]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:15])[CH3:14]>C1COCC1>[F:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([C:13](=[O:15])[CH2:14][C:6](=[O:8])[C:5]([F:4])([F:11])[F:12])[S:17][C:18]=2[CH:24]=1
Reactant: CC(=O)c1nc2ccc(F)cc2s1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1nc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.4 %

Procedure:
To a suspension of sodium methoxide (0.581 mg, 1.08 mmol) in THF (15 ml) was added a solution of ethyl trifluoroacetate (1.456 g, 10.2 mmol) in THF (7 ml) under nitrogen atmosphere. To the resulting mixture was added a solution of 2-acetyl-6-fluorobenzothiazole (2.00 g, 10.2 mmol) in THF (25 ml) dropwise along with ice cooling. The mixture was stirred at room temperature for 1.5 hours, and then concentrated. The resultant residue was subjected to purification using column chromatography on silica gel to afford 1-(6-fluorobenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione (1.26 g, 42%). NMR(CDCl3 -DMSO-d6) δ: 6.85 (1H, s), 7.23 (1H, app dt, J=2.6 Hz, 8.9 Hz), 7.59 (1H, dd, J=2.6 Hz, 8.2 Hz), 8.05 (1H, dd, J=4.6 Hz, 8.9 Hz); mp 175-178° C.
Reaction SMILES: C(O[C:5]1([CH2:10][N:11]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:13]/[C:12]/2=[N:20]\[C:21]([C:23]2[CH:28]=[C:27](Cl)[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=S)[CH2:9]CCC1)(=O)C.C([N:34]([CH2:37]C)CC)C.[N:39]#[C:40][NH2:41]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:16]([C:14]1[S:13]/[C:12](=[N:20]\[C:21]([C:23]2[CH:28]=[C:27]([C:37]#[N:34])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[N:41][C:40]#[N:39])/[N:11]([CH2:10][CH2:5][CH3:9])[CH:15]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: N#CN
Reactant: CCN(CC)CC
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCCC1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC#N
Product: CCCn1cc(C(C)(C)C)s/c1=N\C(=NC#N)c1cc(C#N)ccc1OC
Yield: 73.8 %

Procedure:
The product of Example 24D (0.30 g, 0.80 mmol), triethylamine (0.30 mL, 2.2 mmol), cyanamide (70 mg, 1.6 mmol) and Hg(OAc)2 (0.33 g, 1.0 mmol) in acetonitrile (10 mL) were processed as described in Example 16E to provide the title compound (0.23 g, 0.59 mmol, 73% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.97 (t, J=7.3 Hz, 3H), 1.39 (s, 9H), 1.79-1.92 (m, 2H), 4.00 (s, 3H), 4.17 (dd, J=7.4 Hz, 2H), 6.79 (s, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.64-7.75 (m, 2H); MS (DCI/NH3) m/z 382 (M+H)+. Anal. calculated for C20H23N5OS: C, 62.97; H, 6.08; N, 18.36. Found: C, 62.82; H, 5.91; N, 18.26.
Reaction SMILES: C(OC([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[CH3:15])[CH2:11][O:10]C1(C)C)=O)(C)(C)C>CCO.C(Cl)(Cl)Cl.[Pd]>[NH2:8][C@@H:12]([CH2:13][CH:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:11][OH:10]
Reactant: C/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C[C@H](N)CO)c1ccccc1
Yield: 86.5 %

Procedure:
A solution of (S)-2,2-dimethyl-4-((E)-2-phenyl-propenyl)-oxazolidine-3-carboxylic acid tert-butyl ester (700 mg) in EtOH (30 ml) and CHCl3 (15 ml) was treated with 10% Pd/C (200 mg) and hydrogenated with a balloon overnight. The catalyst was filtered off, washed with EtOH and concentrated. The residue was dissolved in EtOH (10 ml) and treated with 2N HCl (15 ml). The mixture was heated for 90 min to 100° C., then concentrated. The residue was taken up in 1N NaOH and extracted with CH2Cl2/MeOH 4:1. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (S)-2-amino-4-phenyl-pentan-1-ol (342 mg) as off-white waxy solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+:27]([C:30]1[C:31]([S:36]Cl)=[N:32][CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>ClCCl>[CH2:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:36][C:31]1[C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)SSC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1SCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)SSC[C@H](NSc1ncccc1[N+](=O)[O-])C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(R)-2-amino-N-benzyl-3-(tert-butyldisulfanyl)propanamide (Compound tk93) (60 mg, 0.201 mmol) and triethylamine (0.034 ml, 0.241 mmol) were dissolved in dichloromethane (1 ml), and the solution was cooled to 0° C. 3-Nitro-2-pyridinesulfenyl chloride (46.0 mg, 0.241 mmol) was added and the mixture was stirred at 0° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)—N-benzyl-3-(tert-butyldisulfanyl)-2-(((3-nitropyridin-2-yl)thio)amino)propanamide (Compound tk94) (87 mg, 96%).