Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:25]([C:27]1[C:28](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[O:29][C:30]([CH3:34])([CH3:33])[C:31]=1[CH3:32])#[N:26].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:32][C:31]3[C:30]([CH3:33])([CH3:34])[O:29][C:28](=[C:35]([C:36]#[N:37])[C:38]#[N:39])[C:27]=3[C:25]#[N:26])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
In an ethanol/tetrahydrofuran mixed solvent were dissolved 170 mg (0.50 mmol) of 5-[2-[4-(dibutylamino)phenyl]vinyl]thiophene-2-carboaldehyde and 110 mg (0.55 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture, 42 mg of ammonium acetate was added, and the mixture was stirred at room temperature. The solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 198 mg of a black crystal having amp of 208-209° C. (yield: 76.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])=O>C(O)C>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1Br
Solvent: CCO
Product: Brc1ccccc1-c1cn2ccccc2n1

Procedure:
A solution of 2-aminopyridine (1.63 g) and 2-bromo-1-(2-bromophenyl)-ethanone (4.8 g) in dry ethanol (40 mls) was heated under reflux for 1 hour. The mixture was concentrated in vacuo. The residue was treated with dilute sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate was washed with water and brine then dried and evaporated. Flash chromatography produced the sub-title compound as a light grey oil. MS MW 272/274 bp 272.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C@H:19]1[O:21][CH2:20]1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:19]([OH:21])[CH2:20][NH:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH2:9]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: N[C@@H]1CCC[C@@H](c2cccc(O)c2)C1
Solvent: Cc1ccccc1
Product: Oc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of 10 ml of toluene, 1.92 g of (1R,3R)-3-(3-hydroxyphenyl)cyclohexylamine and 1.55 g of (R)-3-chlorostyrene oxide was heated under reflux for 4 hours. The reaction liquid was cooled to room temperature, a seed crystal was inoculated into it, and stirred as such for 30 minutes. The precipitated crystal was taken out through filtration, and then dried under aeration at 50° C. for 2.5 hours to obtain 2.42 g of the entitled compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:19]=[CH:18][N:17]=3)[C:9]=2[N:10]=1)=[O:4].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[N:32]1([CH2:2][C:3]([NH:5][C:6]2[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=5)[N:19]=[CH:18][N:17]=4)[C:9]=3[N:10]=2)=[O:4])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(CCl)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(CN1CCOCC1)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
This material was prepared according to the procedure described in Example 83(b) using 2-chloro-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 83(a)), (0.17 g, 0.33 mmol) and morpholine (72 uL, 0.82 mmol, Aldrich) in CH2Cl2 (1.5 mL). Purification by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 516 (M+1). Mp:177.8-181.7° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH:9]=1)=[O:7])#[N:2].[BH4-].[Na+].O1CCCC1>CO>[C:1]([CH2:3][CH2:4][NH:5][C:6]([CH:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH2:9]1)=[O:7])#[N:2]
Reactant: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCNC(=O)C1CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of 0.33 g of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxamide, 0.20 g of sodium borohydride, 20 ml of tetrahydrofuran and 10 ml of methyl alcohol was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 2N hydrochloric acid was added therein. The resultant mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solution, ethyl acetate:hexane=1.1) to obtain 0.17 g of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-3,4-dihydro-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 137°-138° C.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]([OH:15])[CH:9]=1)[CH3:5].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]([O:15][CH2:1][CH3:2])[CH:9]=1)[CH3:5]
Reactant: CCOC(=O)c1ccc(I)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(I)c(OCC)c1
Temperature: 65 °C

Procedure:
Reflux 3-hydroxy-4-iodo-benzoic acid (38 g, 144 mmol) and saturated solution of HCl in ethanol (600 mL) overnight. Evaporate the solvent yielding 42 g, 99% of 3-hydroxy -4-iodo-benzoic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 7.33 (dd, J=8.3 and 2.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H). Add ethyl iodide (33.8 g, 216 mmol) to a solution of 3-hydroxy -4-iodo-benzoic acid ethyl ester (42 g, 144 mmol) and K2CO3 (39.9 g, 288 mmol) in acetonitrile (400 mL) under magnetic stirring. Heat the reaction mixture at 65° C. for 2 hours, allow the mixture to cool and maintain at RT overnight. Evaporate the solvent and add ethyl acetate to the crude. Filter the solid through Celite® and evaporate the solvent. Yield 42 g, 96%. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 1.50 (t, J=7.0 Hz, 3H), 4.16 (q, J=7.0 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.36 (dd, J=8.1 and 1.8 Hz, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([Cl:19])[C:17]=1[OH:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:12]=[C:11]([Cl:10])[C:17]([OH:18])=[C:16]([Cl:19])[CH:15]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[C:16]([Cl:19])[C:17]=1[OH:18]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Oc1c(Cl)cc(Nc2ncc(F)c(Nc3cc(Cl)c(O)c(Cl)c3)n2)cc1Cl

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,5-dichloro-4-hydroxyaniline gave N2,N4-bis-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 21.26 min.; purity: 88%; MS (m/e): 450 (M+); 1H NMR (DMSO-d6): δ 9.96 (1H, s), 9.59 (1H, s), 9.47 (1H, s), 9.37 (1H, s), 8.22 (1H, d, J=3.6 Hz), 7.79 (2H, s), 7.74 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCNS(=O)(=O)c1cccc(Br)c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 3-bromobenzenesulfonyl chloride (1.00 g, 3.72 mmol) in acetone (10 mL) was added 2-methoxyethylamine (0.97 mL, 11.15 mmol, 3.0 eq) and potassium carbonate (2.57 g, 18.6 mmol, 5.0 eq), and the reaction was stirred at 40° C. for 5 h. The mixture was cooled to room temperature and then partitioned between EtOAc and water, and the organic phase was washed with brine, dried over MgSO4, and concentrated at reduced pressure. The residue was purified by MPLC (20% to 25% EtOAc/hexane) to give 1.05 g (96%) of the desired product as an oil. TLC [30% EtOAc/hexane], Rf=0.33.
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH2:4][CH3:5].I[CH3:22].O>CN(C)C=O>[CH3:22][N:7]([C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N(C)C(=O)CC)cc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a suspension of sodium hydride (60% active, 31 mg) in dimethylformamide (1 ml) was added a solution of ethyl 4-propionamidocinnamate (160 mg) in dimethylformamide (2 ml) at ambient temperature under nitrogen atmosphere. The mixture was stirred for 1 hour at same temperature, and a solution of iodomethane (111 mg) in dimethylformamide (2 ml) was added thereto. The reaction mixture was stirred at same temperature for 2 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 4-(N-methylpropionamido)cinnamate (168 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6](=O)[CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O)[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:6]1[N:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[N:31]=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=12)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:2]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1=O)C1CCCCC1
Solvent: CCO
Product: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.3, 2-cyclohexyl-3-oxo-3-(2-oxo-cycloheptyl)-propionic acid ethyl ester was condensed with (4-chloro-phenyl)-hydrazine (CAS Reg. No. 1073-69-4) in ethanol to give the title compound as orange oil. MS: m/e=415.3 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:20]=[CH:21][C:22]=1F>>[C:24]([C:19]1[CH:20]=[CH:21][C:22]([O:1][C:2]2[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)=[C:17]([Cl:16])[CH:18]=1)(=[O:25])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(c1ccccc1)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(C(=O)c3ccccc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [CH3:1][C@@H:2]([NH:22]C(=O)OC(C)(C)C)[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:22])=[CH:11][CH:10]=2)=[CH:14][C:15]=1[O:20][CH3:21]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-methyl-2-[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate (Intermediate 51, 350 mg) in dry dichloromethane (7.5 mL), TFA (2.5 mL, 32.4 mmol) was slowly added and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge (10 g) to afford the title compound as a colourless oil (258 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[C:18]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[O:40][CH:41]([F:43])[F:42])=[N:17]1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C@@H:9]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[C:18]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[O:40][CH:41]([F:43])[F:42])=[N:17]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reaction time: 0.13 h
Yield: 63.9 %

Procedure:
The mixture of methyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-butanoate (280 mg), in DCM/TFA (15 mL, 2:1) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (24.0% MeCN up to 40.0% in 8 min); Detector, 254/220. 150 mg product was obtained. This resulted in 148.4 mg (73%) of methyl (2S)-2-amino-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoate formate as an off-white solid. LCMS (Method 28) [M+H]+=520.1, RT=0.82 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.68 (m, 2H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.01 (t, 1H, J=73.2 Hz), 4.40-4.26 (m, 2H), 3.64 (s, 3H), 3.50-3.43 (m, 1H), 2.32-2.18 (m, 1H), 2.11-1.99 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:29])[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:29])[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: COc1ccccc(N)c1=O
Solvent: Cc1ccccc1C
Product: COc1ccccc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)c1=O
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (1.5 g) and 2-amino-7-methoxy-2,4,6-cycloheptatrien-1-one (0.8 g) in xylene (25 ml) is refluxed for 6.5 hours. The reaction mixture is then allowed to stand at room temperature overnight. The crystals that have separated out are collected by filtration and recrystallized from dimethylformamide to give 4-hydroxy-2-methyl-N-(7-methoxy-1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2 -benzothiazine-3-carboxamide 1,1-dioxide (0.7 g), m.p. 243°-247° C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C>>[C:9]([O:8][C:6]([NH:5][CH:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=[O:2])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)CC(C=O)NC(=O)OC(C)(C)C

Procedure:
t-Butoxycarbonyl-L-leucine methyl ester was reduced with diisobutylaluminium hydride in an analogous manner to that described in Example 1 to give 2-t-butoxycarbonylamino-4-methyl-valeraldehyde, which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:27]1[C:31](=[O:32])[CH2:30][CH:29]([S:33]([OH:36])(=[O:35])=[O:34])[C:28]1=[O:37].[Na:38].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[Na:38].[CH2:1]([O:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][N:27]1[C:31](=[O:32])[CH2:30][CH:29]([S:33]([OH:36])(=[O:35])=[O:34])[C:28]1=[O:37])=[O:23])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(S(=O)(=O)O)C(=O)N1O
Reactant: O=C(O)CCCCCCCCCCCCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(CCCCCCCCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)O)C1=O)OCc1ccccc1
Reaction time: 2 h
Yield: 41.5 %

Procedure:
In 0.4 ml of anhydrous dimethyl formamide was dissolved 1,14-tetradecanedioic acid monobenzyl ester (100 mg, 0.29 mmole). To the obtained solution were added sodium N-hydroxysulfosuccinimide (63 mg, 0.29 mmole) and a solution of DCC (65 mg, 0.29 mmole) in 0.4 ml of anhydrous dimethylformamide and the resulting mixture was stirred for 14 hours at a room temperature. The reaction mixture was filtered and the filtrate was stirred for 2 hours at a temperature under ice cooling. The solid that formed was collected by filtration and dried under reduced pressure to give N-(13-benzyloxycarbonyltridecanoyloxy)sulfosuccinimide sodium salt (66 mg, 42%) having the following properties.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[NH:1]([C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 96.6 %

Procedure:
56.5 g of 5-acetamino-1,3-benzodioxole in 250 ml of glacial acetic acid were nitrated as described above with a solution of 30 ml of nitric acid in 100 ml of glacial acetic acid in a 500 ml sulfonation flask equipped with stirrer, thermometer and dropping funnel. The crystals, removed by filtration under suction, were ashed thoroughly with water and dried overnight at about 60° C. in vacuo. There were obtained 68.3 g (96.6% of theory) of 5-acetamino-6-nitro-1,3-benzodioxole of melting point 211°-213° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:19]([C:22]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])([O-:21])=[O:20]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cc(CC=O)ccc1[N+](=O)[O-]
Product: COC(=O)c1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(=O)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and Methyl 2-nitro-5-(2-oxoethyl)benzoate following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 457 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)#[N:17].P(Cl)(Cl)(Cl)=O>O>[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:2]([CH3:1])[C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:13]([O-:15])=[O:14])=[O:23])=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(N(C)C(=O)c2ccc(C#N)cc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 13.1 g of methyl 4-methylamino-3-nitro-benzoate, 10.3 g of 4-cyano-benzoylchloride and 75 ml of phosphorusoxychloride is stirred for 8 hours at 100° C. After cooling, the mixture is decomposed with water and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phases are washed with soda solution and concentrated by evaporation. The residue is dissolved in a little acetone and ether is slowly added. The quantities precipitated initially (about 1.2 g) are discarded. After further ether has been added the desired substance is precipitated. Yield: 10.2 g (48% of theory), Rf value: 0.54 (silica gel; ethyl acetate/petroleum ether =7:3)
Reaction SMILES: [OH-].[K+].[C:3]1([C@H:9]([NH2:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(C)=O>O>[C:3]1([CH:9]([NH2:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(N)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Solid, powdered potassium hydroxide (4.6 mg, 8.2×10-5 mol) and (R)-1-phenylethylamine (98% ee) (1.00 g, 8.25×10-3 mol) are mixed with dimethyl sulfoxide (5 ml, 0.07 mol), and the mixture is heated to 80°C. and kept at this temperature for 16 h. The mixture is then cooled and diluted with water (5 ml), and the amine is extracted into ether (2×10 ml). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to give 0.85 g (85%) of substantially racemic 1-phenylethylamine; purity >96% by 1HNMR, ratio (S):(R) recovered by HPLC with chiral column as 1:1.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:8]([OH:10])=O)=[O:5])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:8](=[O:10])[C@H:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)N[C@@H](C(=O)O)C1CCCCC1
Agent: Cl
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Yield: 75.1 %

Procedure:
Reaction of 1.1 g of (R)-ethoxycarbonylamino-cyclohexyl-acetic acid and 1.16 g of (L)-proline benzyl ester hydrochloride according to the procedure described in example 91b gave 1.50 g (75%) of the title compound as a colorless oil. (+)-APCI-MS: 417 (MH+).