Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].[NH2:34][CH2:35][CH2:36][OH:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CO>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:22])([F:24])[F:23])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:34][CH2:35][CH2:36][OH:37])=[O:4]
Reactant: O=C(O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCCO)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Preparation 131B, isomer 1, 40 mg, 0.088 mmol) in DMF (1 mL) was added 2-aminoethanol (8.03 mg, 0.131 mmol), BOP (46.5 mg, 0.105 mmol), and 4-methylmorpholine (53.2 mg, 0.526 mmol). The reaction mixture was stirred for 1 h. Methanol was added and it was purified by prep HPLC (Phenomenex 21.2×250 mm, Solvent A: 90% water with 10% acetonitrile and 0.1% TFA, Solvent B: 90% acetonitrile with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 30 min, 20 mL/min, 220 nM) to yield 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (23 mg, 0.045 mmol, 51.5% yield) as a white solid: product HPLC ret. time=8.83 min (condition G); LC/MS M+1=500.04; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (1H, t, J=5.83 Hz), 7.87 (1H, d, J=7.92 Hz), 7.80 (2H, d, J=7.26 Hz), 7.63-7.75 (3H, m), 7.45-7.52 (2H, m), 6.34 (1H, d, J=4.84 Hz), 4.99 (1H, d, J=4.62 Hz), 4.71 (1H, t, J=5.28 Hz), 3.43 (2H, q, J=5.94 Hz), 3.12-3.24 (2H, m), 3.04 (4H, s).
Reaction SMILES: CCOP(SC[S:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)(OCC)=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>[CH2:12]([SH:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(OCC)SCSc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCS

Procedure:
PTMP--pentarythritol tetrakis (3-mercapto propionate)
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[N:68]1([CH2:74][CH2:75][C:76](O)=[O:77])[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:76](=[O:77])[CH2:75][CH2:74][N:68]2[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]2)=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)CCN5CCCCC5)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 3-(1-piperidinyl)propanoic acid (0.0162 g, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.% trifluoroacetic acid) to give 0.032 g (43%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H), 10.01 (br. s., 1H), 9.01-9.18 (m, 1H), 8.97 (d, 1H), 7.92 (br. s., 1H), 7.68-7.84 (m, 1H), 7.40-7.56 (m, 2H), 7.27-7.41 (m, 2H), 7.15-7.28 (m, 1H), 7.08 (s, 1H), 4.36-4.68 (m, 2H), 3.22-3.48 (m, 4H), 2.67-2.98 (m, 4H), 1.72-1.87 (m, 2H), 1.48-1.71 (m, 3H), 1.20-1.43 (m, 1H). ES MS: m/z 608 (M+1).
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[C:8]([F:19])[CH:7]=1.[N-:20]=[N+:21]=[N-].[Na+].C([O-])(=O)C.[Na+]>Cl>[N:5]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[C:8]([F:19])[CH:7]=1)=[N+:20]=[N-:21]
Reactant: Nc1ccc(N2CCC(=O)CC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Product: [N-]=[N+]=Nc1ccc(N2CCC(=O)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Sodium nitrite (9.9 g, 144 mmol) was added to an ice-cooled solution of 1-(4-amino-2-fluoro-phenyl)-piperidin-4-one (15 g, 72 mmol), obtained in Preparation 10, in 6 N HCl (60 ml) and the resulting solution was stirred at 0° C. for 0.5 h. An aqueous solution of sodium azide (9.4 g, 144 mmol) and sodium acetate (118 g, 1.44 mol) was then added. The reaction mixture was extracted with ethyl acetatc (100 ml×2) and the combined extracts were washed with 5% sodium bicarbonate solution followed by brine and dried over sodium sulfate. Removal of volatiles left a crude product, which was purified by silica gel column chromatography (ethyl acetate/pet. ether, 1:1) to obtain the title azide (10 g, 63%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[S:26][C:25]([SH:27])=[N:24][N:23]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:27][C:25]3[S:26][C:22]([CH3:21])=[N:23][N:24]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Cc1nnc(S)s1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2nnc(C)s2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 5-methyl-1,3,4-thiadiazole-2-thiol. m/e− 367 for C19H19N4S2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.55 (d, J=9.1 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.09 (dd, J=1.4, 9.1 Hz, 1H), 5.83 (s, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 186.983, 156.637, 146.840, 144.588, 138.165, 131.265, 129.597, 128.800, 128.649, 122.931, 122.787, 116.971, 113.923, 44.131, 21.557, 18.638, 16.606 ppm.
Reaction SMILES: O.NN.[F:4][C:5]([F:41])([F:40])[C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19][O:20][N:21]4C(=O)C5=CC=CC=C5C4=O)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:10]=2[CH:39]=1>C(O)C>[NH2:21][O:20][CH2:19][C:16]1[N:15]2[C:9]3[CH:8]=[CH:7][C:6]([C:5]([F:41])([F:40])[F:4])=[CH:39][C:10]=3[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[N:12][CH2:13][C:14]2=[N:18][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)[CH2:22][CH2:21]2)[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].Cl>CO.O>[CH:25]1([NH:24][C:23]([C:20]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)[CH2:22][CH2:21]2)=[O:28])[CH2:27][CH2:26]1
Reactant: COC(=O)C1(CCCCCCCCCCCCC2(C(=O)NC3CC3)CC2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(CCCCCCCCCCCCC2(C(=O)NC3CC3)CC2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of product of Example 34 (0.7 g, 1.9 mmol) in methanol (7 mL) was added KOH (0.36 g, 6.4 mmol) in water (2.1 mL) and the reaction mixture was stirred at 60° C. over a period of 16 h. The crude product obtained upon evaporation of the solvent was diluted with water (5.0 mL), acidified to pH=2 (1.5N HCl), extracted with ethyl acetate (100 mL×2). The organic layer was dried over sodium sulphate and concentrated. The residue obtained upon evaporation of the volatiles was purified by silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product as white solid 0.51 g (76%). mp: 95.3° C.-97.7° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]>CO.[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:33])([F:1])[F:32])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=3)[CH2:17][CH2:18]2)=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-((4-(4-nitrophenoxy)piperidin-1-yl)methyl)phenyl)propan-2-ol (4.01 mmol, 1.92 g) and palladium (10% on carbon, Degussa) (0.040 mmol, 0.085 g) were hydrogenated in methanol (20 mL) at 5 bar for 1 hour at room temperature. The reaction mixture was filtered and the filtrate concentrated under vacuum to afford the title compound. MS (ESI) m/z 449.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH:6](F)[CH2:7][C:8](F)(F)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]C=1.[N:26]1(C(C2C=CC=CC=2)CN)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.ClC1C(C(F)(F)F)=CC=CC=1C=O.FCC(CF)(CF)C(C1C=CC=CC=1)=O>>[Cl:1][C:2]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:8]1[CH:9]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC(c1ccccc1)N1CCOCC1
Reactant: FC(CC(F)(F)c1ccccc1)NCc1cccc(C(F)(F)F)c1Cl
Agent: O=C(c1ccccc1)C(CF)(CF)CF
Agent: O=Cc1cccc(C(F)(F)F)c1Cl
Product: FC(F)(F)c1cccc(CNCC(c2ccccc2)N2CCOCC2)c1Cl

Procedure:
Following the procedure (preparation of rac-±-(2-chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-amine) of Example 64, step (a) except rac-±-2-Morpholin4-yl-2-phenyl-ethylamine was used in step (a) instead of 2-chloro-3-(α,α,α-trifluoromethyl)benzylamine, and 2-chloro-3-trifluoromethyl benzaldehyde was used instead of (α,α,α-trifluoromethylphenylacetaldehyde, the title compound was sythesized as an oil, 0.27 g (88%); MS (ESI) 399 (M+H+).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[Cl:25])=[CH:14][CH:15]=2)[C:10](=[O:26])[C:9]([C:27]([O:29]CC)=[O:28])=[CH:8]1)(=O)C.[OH-].[Na+]>C(O)C>[Cl:25][C:19]1[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH2:6][CH2:5][OH:4])[CH:8]=[C:9]([C:27]([OH:29])=[O:28])[C:10]2=[O:26]
Reactant: CCOC(=O)c1cn(CCOC(C)=O)c2ccc(Cc3cccc(Cl)c3Cl)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(CCO)c2ccc(Cc3cccc(Cl)c3Cl)cc2c1=O
Yield: 88.3 %

Procedure:
Ethyl 1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate obtained in Step 4 (6.0 g, 13.0 mmol) was suspended in ethanol (480 ml) and 4N aqueous sodium hydroxide solution (84 ml, 21 mmol) was added. The mixture was heated under reflux for 30 min. After allowing the mixture to cool, the reaction solution was partly concentrated under reduced pressure. Hydrochloric acid was added and the precipitate was collected by filtration, washed with water and ethanol and vacuum-dried to give an object product (4.5 g, yield 85%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][CH3:16])[N:11]=1)(C)(C)C.[ClH:18]>ClCCl>[ClH:18].[CH2:15]([C:12]1[N:11]=[C:10]([CH2:9][CH2:8][NH2:7])[O:14][N:13]=1)[CH3:16]
Reactant: CCc1noc(CCNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: ClCCl
Product: CCc1noc(CCN)n1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
2.05 g (8.50 mmol) tert-butyl[2-(3-ethyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamate are placed in 20 ml dichloromethane, 40 ml 1 molar ethereal hydrochloric acid are added. The reaction mixture is stirred for 16 hours at ambient temperature and for 4 hours at 40° C. After the addition of a further 10 ml ethereal hydrochloric acid the mixture is stirred for another 72 hours at ambient temperature. The suspension is evaporated down.
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][C:61](O)=[O:62])[CH:54]=1>C(Cl)Cl>[CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:61](=[O:62])[CH2:60][CH2:59][C:55]2[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=2)[C@H:7]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)CCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CCc2cccnc2)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 63.9 %

Procedure:
A solution of (1R,3R,4S)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)-cyclohexane-1,4-diamine (see 30b) (50 mg, 0.154 mmol), 1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDCI) (32 mg, 0.166 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (22 mg, 0.166 mmol), Et3N (17 mg, 0.166 mmol) and 3-(pyridin-3-yl)propanoic acid (26 mg, 0.166 mmol) in CH2Cl2 (5 mL) was stirred overnight at room temperature. The mixture was dilute with CH2Cl2 (20 mL) and washed with water, brine and evaporated. The residue was chromatographed on silica gel (4-6% NH4OH/MeOH/CH2Cl2) to give the product (45 mg, 66%). MS found: (M+1)+: 458.53.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]2)[C:22]1=[O:41].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:33]4=[CH:34][C:35]5[O:39][CH2:38][O:37][C:36]=5[CH:40]=[C:32]4[O:31][CH2:30]3)[C:22]2=[O:41])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(Cl)nc2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using 2-chloro-5-(chloromethyl)pyridine to replace 2-bromomethyl-5-(trifloromethyl)furan, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (69%): 1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 7.63 (dd, 1H), 7.34-7.14 (m, 3H), 7.05 (t, 1H), 6.77 (d, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 5.89-5.84 (m, 2H), 5.07-4.78 (m, 3H), 4.66 (d, 1H); MS (ES+) m/z 407.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Br:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30]Cl)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH2:19][CH3:20])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:30][CH2:29][N:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([Br:22])=[CH:24][CH:25]=2)[CH2:32][CH2:33]1)=[O:21])[CH3:2]
Reactant: CCC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(Br)cc1
Product: CCC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-pent-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 12.9 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (5.83 g, 16.8 mmol, 2.85 g of the product was isolated. Yield 2.85 g (31%); low melting white solid; MS: 549.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[CH:17]([CH3:20])[CH2:18][O:19][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH2:9][C:11]1[C:16]2[CH:17]([CH3:20])[CH2:18][O:19][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OCC2C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCc2c(Cl)cncc2Cl)c2c1OCC2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
Under an argon atmosphere, a solution (28 ml) of Compound 56a (1.0 g) obtained in Step A in methylene chloride was cooled to −78° C., and then boron trifluoride ether complex (0.69 ml) and triethylsilane (1.35 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to give Compound 56 (0.62 g, 64.9%) as pale-yellow oily crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][CH2:26][CH2:27][C:28]1([NH2:31])[CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C:28]4([CH2:27][CH2:26][O:25][CH3:24])[CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: COCCC1(N)CC1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.73 (m, 4 H) 1.79 (t, J=6.9 Hz, 2 H) 3.14 (s, 3 H) 3.39 (t, J=6.9 Hz, 2 H) 7.72 (d, J=8.6 Hz, 2 H) 8.07 (d, J=7.8 Hz, 2 H) 8.27-8.34 (m, 1 H) 8.37 (br. s., 1 H) 8.57 (br. s., 1 H) 8.77 (s, 1 H) 8.79-8.83 (m, 1 H) 13.46 (br. s., 1 H). MS m/z 404 [M+H]+.
Reaction SMILES: COC1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2SC=C(C(OC)=O)N=2)CC1)=O.Cl.[Br:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][N:38]=[C:37]2[C:43]([NH:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:44].Cl[CH2:54][C:55]1[O:59][C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:57][CH:56]=1>>[Br:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][N:38]=[C:37]2[C:43]([NH:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([CH2:54][C:55]2[O:59][C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:57][CH:56]=2)[CH2:51][CH2:52]1)=[O:44]
Reactant: O=C(NCC1CCNCC1)c1n[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Agent: Cl
Product: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1

Procedure:
Ethyl 5-{[4-({[(5-bromo-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}furan-2-carboxylate 15 was prepared, according to the procedure described for compound 7, from 11b and ethyl 5-(chloromethyl)furan-2-carboxylate. Yield: 300 mg, 62%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[N:14][N:15]([CH:17]4[CH2:20][O:19][CH2:18]4)[CH:16]=3)[CH:8]=2)[N:3]1[C:21](=[O:23])[CH3:22].[CH3:24][CH:25]([CH3:30])[CH2:26][C:27](Cl)=[O:28].N1C=CC=CC=1>ClCCl>[C:21]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]3[CH:13]=[N:14][N:15]([CH:17]4[CH2:20][O:19][CH2:18]4)[CH:16]=3)=[CH:6][CH:5]=2)[N:10]([C:27](=[O:28])[CH2:26][CH:25]([CH3:30])[CH3:24])[CH2:11][C@@H:2]1[CH3:1])(=[O:23])[CH3:22]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2NC[C@@H]1C
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)CC(C)C)C[C@@H]1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-1-(2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (50 mg, 0.16 mmol), 3-methylbutanoyl chloride (93 mg, 0.77 mmol), pyridine (63 mg, 0.80 mmol, 5.00 equiv) and dichloromethane (30 mL). The resulting solution stirred for 30 min at 0° C. in a water/ice bath and an additional 3 h at room temperature. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 2-50% ethyl acetate-petroleum ether) to afford (S)-1-(4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)-3-methylbutan-1-one (26.7 mg, 42%) of as light yellow oil. 1H NMR (300 MHz, CD3OD) δ ppm 079 (br s, 3 H), 0.93 (d, J=6.60 Hz, 3 H), 1.18 (d, J=6.30 Hz, 3 H), 1.90-2.10 (m, 1 H), 2.42 (s, 3 H), 2.35-2.43 (m, 1 H), 2.48-2.50 (m, 1 H), 2.51-2.89 (m, 1 H), 4.80-4.95 (m, 2 H), 5.08 (d, J=6.90 Hz, 4 H), 5.55-5.65 (m, 1 H), 7.38-7.45 (m, 1 H), 7.55-7.75 (m, 2 H), 8.03 (s, 1 H), 8.24 (s, 1 H). MS (ESI, pos. ion) m/z 425 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([O-:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH3:4][C:2](=[CH2:3])[C:1]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
275 ml of methacryloyl chloride (2.75 mol=1.1 equiv.) was added dropwise to a cooled suspension of 345 g of 4-nitro aniline (2.5 mol) and 290 g of Na2CO3 (2.75 mol =1.1 equiv.) in 2.5 liter acetone. After completing the addition, stirring was continued for 30 min at 30° C. After TLC inspection the reaction mixture was poured into 15 liter of ice-water under stirring. The precipitate was suction-filtered and washed 3 times with 2.5 liter of demineralised water. After drying at 50° C., 476.5 g of 2-methyl-N-(4-nitro phenyl) acrylamide was obtained.