Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:5]([C:15](O)=[O:16])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(N(C(C)C)C(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(OCC)(=O)C>[OH:37][C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:15]([C:5]1[C:4]([C:18]([F:20])([F:21])[F:19])=[N:3][C:2]([Br:1])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:16]
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a yellow suspension of 1.50 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid in 11 ml dichloromethane was added drop wise 0.608 g 1-chloro-N,N, 2-trimethylpropenylamine and the resulting the yellow solution was stirred at room temperature for 30 min. The resulting orange solution was added dropwise to a cooled (ice bath) solution of 0.522 g (1R,2R)-2-amino-cyclohexanol and 0.7868 g ethyldiisopropylamine in 10 ml ethyl acetate. This red solution was stirred at room temperature for 90 min. To the red solution was added 30 ml 10% aqueous citric acid solution. The layers were separated and the organic layer was purified by chromatography on silica gel with a gradient of heptane: ethyl acetate=1:1 to ethyl acetate to yield 1.56 g of the title compound as yellow crystals. MS (M−H) at 479.0 and 476.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]([CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[C:19]([OH:21])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:65]([O:84][NH2:85])([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>ClCCl>[C:65]([O:84][NH:85][C:19](=[O:21])[C@H:18]([NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:16])[CH2:22][CH2:23][CH2:24][N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])([C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of the title compound of Example 1, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (304 mg, 0.593 mmol) and NMM (0.330 mL, 3.00 mmol) in 10 mL of dichloromethane is treated with 1-hydroxy-7-azabenzotriazole (89 mg, 0.654 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) at RT. After stirring for 30 min, O-tritylhydroxylamine (489 mg, 1.776 mmol) is added, and the reaction is stirred for 16 h. The mixture is partitioned between 60 mL of dichloromethane and 40 mL of water. The organic solution is washed with 30 mL of 1 M aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 4/6—ethyl acetate/hexane) affords 293 mg (64%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid O-tritylhydroxyamide as a waxy solid: NMR(CDCl3) 0.62-0.76 (br m, 1H), 1.08-1.24 (br m, 1H), 1.46-1.65 (br m, 1H), 1.72-1.87 (br m, 1H), 3.65-3.73 (m, 2H), 3.94 (t, 1H, J=8.7), 5.31 (d, 1H, J=9.2), 7.20-7.27 (m, 15H), 7.48 (d, 4H, J=8.4), 7.59 (d, 2H, J=8.5), 7.70 (d, 4H, J=8.3), 7.91 (d, 2H, J=8.3), 8.27 (s, 1H); IR 1770, 1710, 1349, 1166; ESI-MS 770 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][CH2:17][CH2:18]Br>C1CCCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:18][CH2:17][O:16][CH3:15])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COCCN(C(=O)OC(C)(C)C)C1CC=CCC1
Yield: 31 %

Procedure:
Cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (3 g, 15.2 mmol) and 2-bromoethyl methyl ether (1.43 ml, 15.2 mmol) were treated overnight to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=7/1) the title compound (Rf=0.33, 1.2 g, 31% yield) was obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[C:9]1([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccnc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Oc1cccnc1-c1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
To a 1 liter round bottom flask equipped with a nitrogen inlet and a condenser was introduced 25 gm. (143.68 mmol) 2-bromo-3-hydroxypyridine, 19.27 gm. (156 mmol) phenylboronic acid, 5 gm (4.31 mmol) tetrakistriphenylphosphine palladium (0). The contents were dissolved in 300 ml of benzene and 100 ml of 2M aqueous sodium carbonate solution. The reaction mixture was heated under reflux for a period of 18 hours. The mixture was allowed to cool to room temperature and extracted with ethyl acetate (4×100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was taken up in chloroform followed by treatment with ether to afford a solid precipitate. Upon filtration there was obtained 10.4 gm (42%) of 2-phenyl-3-hydroxypyridine. 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H), 7.71 (d, 2H), 7.51–7.40 (m, 2H), 7.22 (d, 2H), 7.15 (m, 1H) ppm. Mass spectrum APCI m/z 172 (p+1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[O:17][CH2:16][CH2:15][NH:14][CH2:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH2:26])[N:20]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:18][C:19]1[CH:24]=[C:23]([N:14]2[CH2:15][CH2:16][O:17][CH:12]([C:9]3[NH:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13]2)[N:22]=[C:21]([NH2:26])[N:20]=1
Reactant: c1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)n1
Yield: 115.1 %

Procedure:
A solution of 2-(4-phenyl-1H-imidazol-2-yl)morpholine (550 mg, 2.07 mmol), 4,6-dichloro-2-pyrimidinamine (339 mg, 2.07 mmol) and Hunig's base (0.901 mL, 5.17 mmol) in ethanol (80 mL) was heated at 85° C. for 5 hours. The mixture was concentrated to afford the crude title compound (850 mg) as a brown oil. LC-MS (ES) m/z=357 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[CH:6][C:5]=1[N:13]1[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14]1.[Cl:21][C:22]1[C:35]([N:36]=[C:37]=S)=[C:34]([Cl:39])[CH:33]=[CH:32][C:23]=1[CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([N:13]2[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14]2)=[CH:6][C:7]2[N:11]([CH3:12])[C:37]([NH:36][C:35]3[C:34]([Cl:39])=[CH:33][CH:32]=[C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]=3[Cl:21])=[N:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N2CCC(F)(F)C2)c(C(=O)OC)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(F)(F)C1

Procedure:
The title compound is prepared in analogy to 6c from methyl-2-[3,3-difluoro-pyrrolidinyl]-4-methylamino-5-amino-benzoate (1.19 g, 4.17 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (1.32 g, 4.17 mmol), DIC (0.65 mL, 4.2 mmol) and DMF (20 mL).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1F)[CH3:2].[O:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1.CC([O-])(C)C.[K+].CO>CN(C=O)C.[Pd].C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[O:21][CH:18]1[CH2:19][CH2:20][O:16][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: OC1CCOC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)ccc1OC1CCOC1

Procedure:
Prepared analogously to example 53a with 2-fluoro-5-nitro-benzic acid ethylester (1 g; 4.69 mmol); tetrahydrofuran-3-ol (379 μL; 4.69 mmol); KOtBu (578 mg; 5.16 mmol) in DMF and for step ii) 10 mL MeOH; 5 mL THF and Pd/C (40 mg), H2 (3 bar).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=3)[CH:11]=[N:10][N:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH:21]1([NH:24][C:25]2[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[C:33](I)[C:28]=3[O:27][N:26]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([NH:24][C:25]2[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]([C:14]4[CH:13]=[C:12]5[C:17](=[CH:16][CH:15]=4)[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])=[N:9][N:10]=[CH:11]5)[C:28]=3[O:27][N:26]=2)[CH2:23][CH2:22]1
Reactant: Cc1ccc2c(NC3CC3)noc2c1I
Reactant: C[C@H]1COCCN1c1nncc2cc(B(O)O)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NC3CC3)noc2c1-c1ccc2c(N3CCOC[C@@H]3C)nncc2c1
Temperature: 130 °C

Procedure:
A mixture of (S)-1-(3-methylmorpholino)phthalazin-6-ylboronic acid (0.11 g, 0.41 mmol), N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (0.100 g, 0.32 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 0.016 mmol) in 1,4-dioxane (2.0 mL) and 2 N aqueous sodium carbonate (0.2 mL, 0.4 mmol) in a sealed glass tube was heated in a Personal Chemistry microwave at 130° C. for 20 min. The mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate: chloroform 80:20) afforded the titled compound as a yellow solid. MS (ESI, pos.ion) m/z: 416.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][CH:10]1[CH2:24][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:1]([N:8]([CH3:26])[C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)C1CCN(CCc2ccc(F)cc2)CC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Reaction time: 1.75 h
Yield: 108.8 %

Procedure:
A solution of -{4-(benzyl-methyl-amino)-1-[2-(4-fluorophenyl)-ethyl]-piperidin-3-yl}-methanol (105 mg, 294 μmol) and triethylamine (62 μL, 442 μmol) in dichloromethane (1 mL) was stirred on an ice bath and treated with a solution of methanesulfonyl chloride (25 μL, 320 μmol) in dichloromethane (0.5 mL). After 1.75 hours, the mixture was concentrated and the residue was dissolved in ethyl acetate. The suspension was filtered, the solid was rinsed with ethyl acetate, and the filtrate was concentrated under vacuum to provide a yellowish gum (139 mg) which was used without purification. 1H NMR (300 MHz, CDCl3) δ7.32 (m, 5H), 7.17 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.57 (dd, J=10, 3 Hz, 1H), 4.29 (m, 1H), 3.72 (d, J=13 Hz, 1H), 3.50 (d, J=13 Hz, 1H), 3.4-3.1 (m, 2H), 3.00 (s, 3H), 2.83 (m, 2H), 2.70 (m, 2H), 2.48 (m, 1H), 2.35 (m, 1H), 2.22 (s, 3H), 2.07 (m, 2H), 2.0-1.7 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=CC(OCC)=O)=[CH:6]1.CN(CCC1C=CC=CC=1)C(=O)CC1C=C2C(=CC=1)N(OCC1C=CC=CC=1)C=[C:45]2[CH:59]=[C:60]([C:62]([O:64]CC)=[O:63])C.CN(CCC1C=CC=CC=1)C(=O)CN1C2C(=CC(OCC3C=CC=CC=3)=CC=2)C(C=C(C(O)=O)C=C)=C1>CC(C)=O.CCOCC>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:45][CH:59]=[CH:60][C:62]([OH:64])=[O:63])=[CH:6]1
Reactant: CCOC(=O)C(C)=Cc1cn(OCc2ccccc2)c2ccc(CC(=O)N(C)CCc3ccccc3)cc12
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: C=CC(=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12)C(=O)O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC=CC(=O)O)c2cc(OCc3ccccc3)ccc21

Procedure:
When N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamide in the procedure of Example 23 is replaced with N-methyl-N-phenethyl-2-[1-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-5-yl]acetamide then the product prepared is N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-1,3-butadienyl)indol-1-yl]acetamide. (solvent system (acetone/ether) m.p. 189°-190° C.)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(C)cc1-n1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2'-Hydroxy-5-methylphenyl)2H-benzotriazole(Tinuvin P manufactured by Ciba Geigy Co., Ltd., λmax=336 nm) 1.13 part and triethylamine 0.61 part were dissolved in acetonitrile 20 parts. A solution of acetyl chloride 0.43 part/acetonitrile 10 parts was dropped thereto while cooling with ice. After stirring at a room temperature for further 4 hours, the solution was poured into water 200 parts and extracted with chloroform, followed by condensing and refining with recrystallization (isopropyl alcohol/chloroform). A pale yellow crystal 0.9 part of 2-(2'-acetoxy-5-methylphenyl)2H-benzotriazole was obtained. (λmax=298 nm).
Reaction SMILES: CS[C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>C(O)CCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH:17][C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1
Reactant: CSC1=Nc2ccccc2CS1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCCCO
Product: Clc1ccc(NC2=Nc3ccccc3CS2)cc1Cl
Yield: 43.7 %

Procedure:
A mixture of 2-methylthio-4H-3,1-benzothiazine (39 g, 0.20 mole) and 3,4-dichloroaniline (32.4 g, 0.20 mole) in n-butanol (150 ml) was refluxed overnight. After cooling in ice, the solid was collected by filtration and recrystallized from ethanol to give 27 g (43.8%) of product. Recrystallization from ethanol gave analytical sample m.p. 207°-208°.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:12].C(Cl)(Cl)Cl>O1CCCC1>[C:1]1([C:7]2[CH:11]=[CH:10][SH:9]([CH:6]([OH:12])[CH2:1][CH2:2][CH3:3])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccsn2)cc1
Reactant: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCC(O)[SH]1C=CC(c2ccccc2)=N1
Reaction time: 1 h

Procedure:
Dissolved in 60 ml of anhydrous tetrahydrofuran were 3.1 g (19.1 mmol) of 3-phenylisothiazole, followed by the addition 18.2 ml of an n-butyl lithium-hexane solution (1.57 mol/l) under a nitrogen gas stream at -78° C. over a dry ice-acetone bath. After the resulting mixture was stirred for 1 hour, 1.51 g (21 mmol) of butylaldehyde were added dropwise. The solution was stirred for 1 hour at the same temperature, whereby the reaction was completed. Water and chloroform were added. The reaction product was extracted into an organic layer. The organic layer was concentrated and the concentrate was purified by silica gel chromatography (eluent: 20:1 n-hexane/ethyl acetate), so that 3-phenyl-5-(1-hydroxybutyl)isothiazole was obtained as yellow oil.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:21][CH2:20][CH2:19][C@H:14]1[C:15]([O:17]C)=[O:16])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[OH-].[Na+]>O.CC(C)=O>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:21][CH2:20][CH2:19][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
3 (4.2 g, 9.6 mmol) was dissolved in 30 ml of water/acetone (1/5 v/v) and 11.6 ml NaOH (1N) where added. After completion of the reaction the organic solvent was removed by evaporation and the resulting solution was diluted by 15 ml NaHCO3 solution (saturated). Then the mixture was extracted three times by 10 ml of acetic acid ethyl ester. After that the solution was brought to pH2 by adding HCl (15% in water). The resulting mixture was extracted three times by 30 ml of acetic acid ethyl ester. The organic layer was separated and washed three times with brine, dried (Na2SO4) and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:36])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@H:16]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])[S:10][C:11]=1[CH3:12].NN>O1CCCC1.CO>[NH2:25][CH2:24][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([CH3:12])=[C:7]([C:6]2[N:5]([CH3:36])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:14])[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc(C(=O)N[C@H](CN)CC2CCCCC2)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 61.4 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol) in tetrahydrofuran (2.20 ml) and methanol (2.20 ml) at 25° C. was added hydrazine (0.14 ml, 4.40 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (124 mg, 0.27 mmol, 60% yield) as a yellow solid: LCMS (ES) m/z=394, 396 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (br. s., 1H) 7.97 (br. s., 3H) 7.86 (s, 1H) 7.70 (s, 1H) 4.24-4.26 (m, 1H) 3.71 (s, 3H) 2.90-2.99 (m, 2H) 2.36 (s, 3H) 1.75-1.79 (m, 1H) 1.61-1.64 (m, 4H) 1.48-1.51 (m, 1H) 1.31-1.36 (m, 2H) 1.10-1.14 (m, 2H) 0.91-0.94 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)=[O:4].[C:22](OC(=O)C)(=[O:24])[CH3:23].[H][H]>[Pd].C(O)(=O)C>[F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:22](=[O:24])[CH3:23])=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C(O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1

Procedure:
A mixture of 60.8 g (0.2 Mol) of N-trifluoroacetyl-4-nitro-phenylalanine, 250 ml of glacial acetic acid, 94 ml (1.0 Mol) of acetic anhydride and 10 g 10% palladium/charcoal is hydrogenated for 5 hours at 50° C. under 5 bars of hydrogen. The mixture is then suction filtered and the filtrate is evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][NH:27][CH3:28].CN1CCCC1=O.Cl>[Cl-].[Na+].O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][N:27]([CH3:28])[CH3:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CNC
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN(C)C[C@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (133 mg), dimethylamine (40% solution in water, 3 mL) and 1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in a sealed tube for 22 hours, cooled and poured into brine (50 mL), extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by Waters' MCX resin and then by reverse phase HPLC (gradient 25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid on Waters' Xterra™ column). The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the titled compound as a solid (41 mg).